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**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, DC 20460**

OFFICE OF

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

> April 7, 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**

[**1.0** **EXECUTIVE SUMMARY** 4](#__RefHeading___Toc195349007)

[**2.0** **PHYSICAL AND CHEMICAL PROPERTIES**
14](#__RefHeading___Toc195349008)

[**3.0** **HAZARD CHARACTERIZATION** 14](#__RefHeading___Toc195349009)

[**3.1** **Hazard Profile** 14](#__RefHeading___Toc195349010)

[**3.2** **FQPA Considerations** 15](#__RefHeading___Toc195349011)

[**3.3** **Dose-Response Assessment** 16](#__RefHeading___Toc195349012)

[**3.4** **Endocrine Disruption** 19](#__RefHeading___Toc195349013)

[**4.0** **EXPOSURE ASSESSMENT AND CHARACTERIZATION**
19](#__RefHeading___Toc195349014)

[**4.1** **Summary of Registered Uses**
19](#__RefHeading___Toc195349015)

[**4.2** **Dietary Exposure and Risk** 20](#__RefHeading___Toc195349016)

[**4.3** **Drinking Water Exposures and Risks**
20](#__RefHeading___Toc195349017)

[**4.4** **Residential Exposure/Risk Pathway**
20](#__RefHeading___Toc195349018)

[**5.0 AGGREGATE RISK ASSESSMENT AND CHARACTERIZATION**
28](#__RefHeading___Toc195349019)

[**6.0** **CUMULATIVE EXPOSURE AND RISK**
28](#__RefHeading___Toc195349020)

[**7.0** **OCCUPATIONAL EXPOSURE ASSESSMENT**
29](#__RefHeading___Toc195349021)

[**7.1** **Occupational Handler Exposures**
29](#__RefHeading___Toc195349022)

[**7.2** **Occupational Handler Risk Summary and Characterization**
33](#__RefHeading___Toc195349023)

[**7.3** **Occupational Post-application Exposures**
34](#__RefHeading___Toc195349024)

[**8.0** **HUMAN HEALTH RISK MITIGATION RECOMMENDATIONS**
35](#__RefHeading___Toc195349025)

[**9.0** **ENVIRONMENTAL RISKS** 37](#__RefHeading___Toc195349026)

[**9.1** **Ecological Hazard** 37](#__RefHeading___Toc195349027)

[**9.2** **Environmental Fate Assessment**
44](#__RefHeading___Toc195349028)

[**9.3** **Environmental Exposure and Ecological Risk Assessment**
45](#__RefHeading___Toc195349029)

[**9.4** **Endangered Species Considerations**
45](#__RefHeading___Toc195349030)

[**10.0** **INCIDENT REPORTS** 46](#__RefHeading___Toc195349031)

[**11.0** **REFERENCES** 48](#__RefHeading___Toc195349032)

**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**

[]{#__RefHeading___Toc195349007 .anchor}**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/m^3^ 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/m^3^, respectively), for 6hrs/day, 5 days/week for 13 weeks.
The systemic LOAEL was 12.7 ppm (15.74 mg/m^3^), 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/m^3^) 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/m^3^ dose level dose level while
necrosis and sloughing of the mucosa in the turbinates, trachea, and
proximal bronchi were seen the 61.96 mg/m^3^ 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
F~1~ (B6C3F~1~) 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/m^3^), 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/m^3^), 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/m^3^) 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 B6C3F~1~ 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 \[^14^C\]-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/m^3^) 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/m^3^)
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/m^3^) 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/m^3^) via
inhalation for 3 hours on two days. Exposure to 5 ppm (6.20 mg/m^3^)
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.

**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]{.underline}

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]{.underline}

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]{.underline}

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]{.underline}

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]{.underline}

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]{.underline}

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]{.underline}

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.

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

[Paraformaldehyde Risks]{.underline}

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.

[]{#__RefHeading___Toc195349008 .anchor}**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             |                          |                        |
| Par             |                          |                        |
| aformaldehyde** |                          |                        |
+-----------------+--------------------------+------------------------+
| **Parameter**   | **Formaldehyde**         | **Paraformaldehyde**   |
+-----------------+--------------------------+------------------------+
| **PC Chemical   | 043001                   | 043002                 |
| Code**          |                          |                        |
+-----------------+--------------------------+------------------------+
| **CAS Number**  | 50-00-0                  | 30525-89-4             |
+-----------------+--------------------------+------------------------+
| **Molecular     | CH~2~O (Gas or anhydrous | HO(CH~2~O)~n~H (n =    |
| Formula**       | form)                    | 6 - 100 )              |
|                 |                          |                        |
|                 | H~2~C(OH)~2~ or          |                        |
|                 | C~1~H~4~O~2~             |                        |
|                 | (Formaldehyde            |                        |
|                 | monohydrate)             |                        |
+-----------------+--------------------------+------------------------+
| **Chemical      | Formaldehyde (Gas)       | Paraformaldehyde       |
| Name**          |                          |                        |
|                 | Formaldehyde monohydrate |                        |
|                 | (Aqueous solution)       |                        |
+-----------------+--------------------------+------------------------+
| **Synonyms**    | Formaldehyde, Formalin   | Paraformaldehyde       |
+-----------------+--------------------------+------------------------+
| **Structure**   | ![                       | ![](me                 |
|                 | ](media/image2.png){widt | dia/image3.png){width= |
|                 | h="1.4270833333333333in" | "1.2493055555555554in" |
|                 | height                   | height="               |
|                 | ="0.7819444444444444in"} | 0.7618055555555555in"} |
|                 |                          |                        |
|                 | [www.chemvip.com](       | [www.answers.com](ht   |
|                 | http://www.chemvip.com/) | tp://www.answers.com/) |
+-----------------+--------------------------+------------------------+

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

[]{#__RefHeading___Toc195349009 .anchor}**3.0 HAZARD CHARACTERIZATION**

[]{#__RefHeading___Toc195349010 .anchor}**3.1 Hazard Profile**

[Acute Toxicity]{.underline}

[Adequacy of database for Acute Toxicity]{.underline}: 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  |                      |       |                     |      |
| To     |                      |       |                     |      |
| xicity |                      |       |                     |      |
| Data   |                      |       |                     |      |
| for    |                      |       |                     |      |
| Formal |                      |       |                     |      |
| dehyde |                      |       |                     |      |
| Tec    |                      |       |                     |      |
| hnical |                      |       |                     |      |
| a.i.** |                      |       |                     |      |
+========+======================+=======+=====================+======+
| **Gui  | **Study Type/ Test   | **M   | **Results**         | **   |
| deline | substance**          | RID** |                     | Toxi |
| Nu     |                      |       |                     | city |
| mber** | **(% a.i.)**         | **Nu  |                     | Ca   |
|        |                      | mber/ |                     | tego |
|        |                      | Citat |                     | ry** |
|        |                      | ion** |                     |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Acute Oral -- Guinea | 000   | LD~50~ = 260 mg/kg  | II   |
| 0.1100 | Pig                  | 58054 |                     |      |
|        |                      |       |                     |      |
| (      | Purity 37.3% -       |       |                     |      |
| §81-1) | Formaldehyde         |       |                     |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Acute Dermal -- Rat  | 000   | Number range        | II   |
| 0.1200 |                      | 58054 | CHAPTERLD~50~ = 300 |      |
|        | Purity 37.3% -       |       | mg/kg               |      |
| (      | Formaldehyde         |       |                     |      |
| §81-2) |                      |       |                     |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Acute Dermal --      | 000   | Number range        | II   |
| 0.1200 | Rabbit               | 58054 | CHAPTERLD~50~ = 240 |      |
|        |                      |       | mg/kg               |      |
| (      | Purity 37.3% -       |       |                     |      |
| §81-2) | Formaldehyde         |       |                     |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Acute Dermal -- Dog  | 000   | Number range        | II   |
| 0.1200 |                      | 58054 | CHAPTERLD~50~ = 550 |      |
|        | Purity 37.3% -       |       | mg/kg               |      |
| (      | Formaldehyde         |       |                     |      |
| §81-2) |                      |       |                     |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Acute Inhalation --  | See   |                     |      |
| 0.1300 | Mouse and Rat        | Open  |                     |      |
|        |                      | Liter |                     |      |
| (      |                      | ature |                     |      |
| §81-3) |                      | st    |                     |      |
|        |                      | udies |                     |      |
|        |                      | in    |                     |      |
|        |                      | Tox   |                     |      |
|        |                      | icity |                     |      |
|        |                      | Pr    |                     |      |
|        |                      | ofile |                     |      |
|        |                      | for   |                     |      |
|        |                      | Fo    |                     |      |
|        |                      | rmald |                     |      |
|        |                      | ehyde |                     |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Primary Eye          | 000   | Severe eye irritant | I    |
| 0.2400 | Irritation -         | 58054 |                     |      |
|        |                      |       |                     |      |
| (      | Purity 37.3% -       |       |                     |      |
| §81-4) | Formaldehyde         |       |                     |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Primary Dermal       | 000   | Formation of        | I    |
| 0.2500 | Irritation --        | 58054 | vesicles with       |      |
|        |                      |       | superficial         |      |
| (      | Purity 37.3% -       |       | necrosis or         |      |
| §81-5) | Formaldehyde         |       | nodules.            |      |
+--------+----------------------+-------+---------------------+------+
| 87     | Dermal Sensitization | 401   | Extreme Sensitizer  | NA   |
| 0.2600 | -- Guinea pigs       | 61103 |                     |      |
|        |                      |       |                     |      |
| (      | Purity 40.0% -       |       |                     |      |
| §81-6) | Formaldehyde         |       |                     |      |
+--------+----------------------+-------+---------------------+------+

NA -- Not Applicable

[]{#__RefHeading___Toc195349011 .anchor}**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 ([www.nicnas.gov.au](http://www.nicnas.gov.au/)) as well as
the Agency for Toxic Substances and Disease Registry (ATSDR,
1999)support this conclusion.

[]{#__RefHeading___Toc195349012 .anchor}**3.3 Dose-Response Assessment**

**3.3.1 Summary of Toxicological Endpoints for Formaldehyde**

+--------------+---------------+-----------------+--------------------+
| **Table 3.2. |               |                 |                    |
| Summary of   |               |                 |                    |
| T            |               |                 |                    |
| oxicological |               |                 |                    |
| Doses and    |               |                 |                    |
| Endpoints    |               |                 |                    |
| for          |               |                 |                    |
| Fo           |               |                 |                    |
| rmaldehyde** |               |                 |                    |
+==============+===============+=================+====================+
| Number range | **Dose Used   | **Target MOE,   | **Study and        |
| CHAPTER      | in Risk       | UF,**           | Toxicological      |
| **Exposure** | Assessment**  |                 | Effects**          |
|              |               | **Special FQPA  |                    |
| **Scenario** | **            | SF\* for Risk   |                    |
|              | (mg/kg/day)** | Assessment**    |                    |
+--------------+---------------+-----------------+--------------------+
| **Dietary    |               |                 |                    |
| Risk         |               |                 |                    |
| A            |               |                 |                    |
| ssessments** |               |                 |                    |
+--------------+---------------+-----------------+--------------------+
| **Acute      | An acute      |                 |                    |
| Dietary**    | dietary       |                 |                    |
|              | assessment is |                 |                    |
| (general     | not needed    |                 |                    |
| population   | for the       |                 |                    |
| including    | registered    |                 |                    |
| infants and  | antimicrobial |                 |                    |
| children)    | uses of       |                 |                    |
|              | formaldehyde. |                 |                    |
+--------------+---------------+-----------------+--------------------+
| **Chronic    | A chronic     |                 |                    |
| Dietary**    | dietary       |                 |                    |
|              | assessment is |                 |                    |
| (all         | not needed    |                 |                    |
| populations) | for the       |                 |                    |
|              | registered    |                 |                    |
|              | antimicrobial |                 |                    |
|              | uses of       |                 |                    |
|              | formaldehyde. |                 |                    |
+--------------+---------------+-----------------+--------------------+
| *            |               |                 |                    |
| *Non-Dietary |               |                 |                    |
| Risk         |               |                 |                    |
| A            |               |                 |                    |
| ssessments** |               |                 |                    |
+--------------+---------------+-----------------+--------------------+
| **Incidental | An incidental |                 |                    |
| Oral**       | oral risk     |                 |                    |
|              | assessment is |                 |                    |
|              | not required  |                 |                    |
|              | for the       |                 |                    |
|              | registered    |                 |                    |
|              | antimicrobial |                 |                    |
|              | uses of       |                 |                    |
|              | formaldehyde. |                 |                    |
+--------------+---------------+-----------------+--------------------+
| **Dermal**   | A dermal risk |                 |                    |
| (all         | assessment is |                 |                    |
| durations)   | not required  |                 |                    |
|              | for the       |                 |                    |
|              | registered    |                 |                    |
|              | antimicrobial |                 |                    |
|              | uses of       |                 |                    |
|              | formaldehyde. |                 |                    |
+--------------+---------------+-----------------+--------------------+
| **           | **NOAEL**     | **UF = 1        | ACGIH 2001         |
| Inhalation** | (human) = 0.1 | (               | publication on     |
|              | ppm           | occupational)** | formaldehyde       |
| (all         |               |                 |                    |
| durations)   |               | **UF = 10       | Horvath, E.P. et   |
|              |               | (residential)** | 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/m^3^) 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 cm^2^ 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 cm^2^ 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/m^3^) 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. However, the panel cautioned NCEA on the potential for
    under-estimation of risk in the CIIT modeling.

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-   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.

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-   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
    (<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/m^3^) 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.

[]{#__RefHeading___Toc195349013 .anchor}**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.

[]{#__RefHeading___Toc195349014 .anchor}**4.0 EXPOSURE ASSESSMENT AND
CHARACTERIZATION**

[]{#__RefHeading___Toc195349015 .anchor}**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.

[]{#__RefHeading___Toc195349016 .anchor}**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.

[]{#__RefHeading___Toc195349017 .anchor}**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.

[]{#__RefHeading___Toc195349018 .anchor}**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             Handler Exposure While Using 1000 ppm product
  Preservation of      Treated Laundry Detergent    
  Laundry Detergent                                 

  Material             Handler Exposure While Using 150 ppm product
  Preservation of      Treated General Purpose      
  Floor and Furniture  Cleaners                     
  Polish and Detergent                              
  Products                                          

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

                       Post Application Exposure    
                       from Wallpaper Adhesive      

  **Inhalation                                      
  Exposures from                                    
  Paraformaldehyde                                  
  Uses**                                            

  Mildewcide for       Post Application Exposure    4 ounce of product per
  clothing and linen                                750 ft^3^
  in closets                                        

  Mildewcide for       Post Application Exposure    4 ounce of product per
  Vacation Homes                                    750 ft^3^
  ------------------------------------------------------------------------

**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.]{.underline} 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]{.underline}

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

<table style="width:100%;">
<colgroup>
<col style="width: 15%" />
<col style="width: 0%" />
<col style="width: 28%" />
<col style="width: 0%" />
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Non-Cancer Risks from Daily
Exposures</strong></td>
</tr>
<tr class="even">
<td colspan="2">Weight Fraction</td>
<td colspan="2"><p>Amount Used Per Day/</p>
<p>Duration of Use</p></td>
<td colspan="2">Exposure Duration</td>
<td colspan="2">Peak Concentration</td>
<td colspan="2"><p>MOE<sup>C</sup></p>
<p>(target MOE = 10)</p></td>
</tr>
<tr class="odd">
<td>0.00037</td>
<td colspan="2">400 grams/0.667 hours<sup>A</sup></td>
<td colspan="2">One day per event</td>
<td colspan="2">240 ppb</td>
<td colspan="3">0.4</td>
</tr>
<tr class="even">
<td colspan="10"><strong>Cancer Risks from Lifetime
Exposures</strong></td>
</tr>
<tr class="odd">
<td rowspan="2">Weight Fraction</td>
<td colspan="2" rowspan="2"><p>Amount Used Per Day/</p>
<p>Duration of Use</p></td>
<td colspan="2" rowspan="2">Frequency of Use</td>
<td colspan="2" rowspan="2">LADC<sup>D</sup></td>
<td colspan="3">Cancer Risk</td>
</tr>
<tr class="even">
<td colspan="2">IRIS<sup>E</sup></td>
<td>CIIT<sup>F</sup></td>
</tr>
<tr class="odd">
<td>0.00037</td>
<td colspan="2">200 grams/0.333 hours<sup>B</sup></td>
<td colspan="2">104 times per year</td>
<td colspan="2"><p>0.5 ppb</p>
<p>(0.61 ug/m<sup>3</sup>)</p></td>
<td colspan="2">8 x 10<sup>-6</sup></td>
<td>&lt;3 x 10<sup>-9</sup></td>
</tr>
<tr class="even">
<td colspan="10"><p>A. High end default assumptions as listed in the CEM
Model documentation.</p>
<p>B. Central tendency default assumptions as listed in the CEM Model
documentation.</p>
<p>C. MOE = NOAEL/Peak Concentration where the NOAEL = 0.1 ppm (100
ppb).</p>
<p>D. LADC = Lifetime Average Daily Concentration assuming exposure 104
days per year and 57 years per 75 year lifetime.</p>
<p>E. Cancer Risk = LADC * Unit Risk, where the Unit Risk = 1.3 x
10<sup>-5</sup> per ug/m<sup>3</sup> as listed in IRIS</p>
<p>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<sup>-9</sup> based on the
Hockey stick shaped CRCP for non-smokers exposed continuously to 0.001
ppm (i.e. 1 ppb)</p></td>
</tr>
</tbody>
</table>

**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]{.underline}

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-C |                   |            |           |       |      |
| ancer |                   |            |           |       |      |
| Risks |                   |            |           |       |      |
| from  |                   |            |           |       |      |
| Daily |                   |            |           |       |      |
| E     |                   |            |           |       |      |
| xposu |                   |            |           |       |      |
| res** |                   |            |           |       |      |
+-------+-------------------+------------+-----------+-------+------+
| W     | Amount Used Per   | Exposure   | Peak      | M     |      |
| eight | Day/              | Duration   | Conc      | OE^C^ |      |
| Fra   |                   |            | entration |       |      |
| ction | Duration of Use   |            |           | (t    |      |
|       |                   |            |           | arget |      |
|       |                   |            |           | MOE = |      |
|       |                   |            |           | 10)   |      |
+-------+-------------------+------------+-----------+-------+------+
| 0.0   | 123 grams/1.42    | One day    | 21 ppb    | 4.8   |      |
| 00055 | hours^A^          | per event  |           |       |      |
+-------+-------------------+------------+-----------+-------+------+
| **C   |                   |            |           |       |      |
| ancer |                   |            |           |       |      |
| Risks |                   |            |           |       |      |
| from  |                   |            |           |       |      |
| Lif   |                   |            |           |       |      |
| etime |                   |            |           |       |      |
| E     |                   |            |           |       |      |
| xposu |                   |            |           |       |      |
| res** |                   |            |           |       |      |
+-------+-------------------+------------+-----------+-------+------+
| W     | Amount Used Per   | Frequency  | LADC^D^   | C     |      |
| eight | Day/              | of Use     |           | ancer |      |
| Fra   |                   |            |           | Ri    |      |
| ction | Duration of Use   |            |           | sk^E^ |      |
+-------+-------------------+------------+-----------+-------+------+
|       |                   |            |           | IR    | CII  |
|       |                   |            |           | IS^E^ | T^F^ |
+-------+-------------------+------------+-----------+-------+------+
| 0.0   | 61.5 grams/0.667  | 52 days    | 0.12 ppb  | 2 x   | \<3  |
| 00055 | hours^B^          | per year   |           | 1     | x    |
|       |                   |            | (0.17     | 0^-6^ | 10   |
|       |                   |            | ug/m^3^)  |       | ^-9^ |
+-------+-------------------+------------+-----------+-------+------+
| A.    |                   |            |           |       |      |
| High  |                   |            |           |       |      |
| end   |                   |            |           |       |      |
| de    |                   |            |           |       |      |
| fault |                   |            |           |       |      |
| a     |                   |            |           |       |      |
| ssump |                   |            |           |       |      |
| tions |                   |            |           |       |      |
| as    |                   |            |           |       |      |
| l     |                   |            |           |       |      |
| isted |                   |            |           |       |      |
| in    |                   |            |           |       |      |
| the   |                   |            |           |       |      |
| CEM   |                   |            |           |       |      |
| Model |                   |            |           |       |      |
| docu  |                   |            |           |       |      |
| menta |                   |            |           |       |      |
| tion. |                   |            |           |       |      |
|       |                   |            |           |       |      |
| B.    |                   |            |           |       |      |
| Ce    |                   |            |           |       |      |
| ntral |                   |            |           |       |      |
| ten   |                   |            |           |       |      |
| dency |                   |            |           |       |      |
| de    |                   |            |           |       |      |
| fault |                   |            |           |       |      |
| a     |                   |            |           |       |      |
| ssump |                   |            |           |       |      |
| tions |                   |            |           |       |      |
| as    |                   |            |           |       |      |
| l     |                   |            |           |       |      |
| isted |                   |            |           |       |      |
| in    |                   |            |           |       |      |
| the   |                   |            |           |       |      |
| CEM   |                   |            |           |       |      |
| Model |                   |            |           |       |      |
| docu  |                   |            |           |       |      |
| menta |                   |            |           |       |      |
| tion. |                   |            |           |       |      |
|       |                   |            |           |       |      |
| C.    |                   |            |           |       |      |
| MOE = |                   |            |           |       |      |
| NOAEL |                   |            |           |       |      |
| /Peak |                   |            |           |       |      |
| Con   |                   |            |           |       |      |
| centr |                   |            |           |       |      |
| ation |                   |            |           |       |      |
| where |                   |            |           |       |      |
| the   |                   |            |           |       |      |
| NOAEL |                   |            |           |       |      |
| = 0.1 |                   |            |           |       |      |
| ppm   |                   |            |           |       |      |
| (100  |                   |            |           |       |      |
| ppb). |                   |            |           |       |      |
|       |                   |            |           |       |      |
| D.    |                   |            |           |       |      |
| LADC  |                   |            |           |       |      |
| =     |                   |            |           |       |      |
| Lif   |                   |            |           |       |      |
| etime |                   |            |           |       |      |
| Av    |                   |            |           |       |      |
| erage |                   |            |           |       |      |
| Daily |                   |            |           |       |      |
| Con   |                   |            |           |       |      |
| centr |                   |            |           |       |      |
| ation |                   |            |           |       |      |
| ass   |                   |            |           |       |      |
| uming |                   |            |           |       |      |
| exp   |                   |            |           |       |      |
| osure |                   |            |           |       |      |
| 52    |                   |            |           |       |      |
| days  |                   |            |           |       |      |
| per   |                   |            |           |       |      |
| year  |                   |            |           |       |      |
| and   |                   |            |           |       |      |
| 57    |                   |            |           |       |      |
| years |                   |            |           |       |      |
| per   |                   |            |           |       |      |
| 75    |                   |            |           |       |      |
| year  |                   |            |           |       |      |
| life  |                   |            |           |       |      |
| time. |                   |            |           |       |      |
|       |                   |            |           |       |      |
| E.    |                   |            |           |       |      |
| C     |                   |            |           |       |      |
| ancer |                   |            |           |       |      |
| Risk  |                   |            |           |       |      |
| =     |                   |            |           |       |      |
| LADC  |                   |            |           |       |      |
| \*    |                   |            |           |       |      |
| Unit  |                   |            |           |       |      |
| Risk, |                   |            |           |       |      |
| where |                   |            |           |       |      |
| the   |                   |            |           |       |      |
| Unit  |                   |            |           |       |      |
| Risk  |                   |            |           |       |      |
| = 1.3 |                   |            |           |       |      |
| x     |                   |            |           |       |      |
| 1     |                   |            |           |       |      |
| 0^-5^ |                   |            |           |       |      |
| per   |                   |            |           |       |      |
| ug    |                   |            |           |       |      |
| /m^3^ |                   |            |           |       |      |
|       |                   |            |           |       |      |
| F.    |                   |            |           |       |      |
| CIIT  |                   |            |           |       |      |
| C     |                   |            |           |       |      |
| ancer |                   |            |           |       |      |
| Risk  |                   |            |           |       |      |
| is    |                   |            |           |       |      |
| taken |                   |            |           |       |      |
| from  |                   |            |           |       |      |
| Table |                   |            |           |       |      |
| 8 of  |                   |            |           |       |      |
| Co    |                   |            |           |       |      |
| nolly |                   |            |           |       |      |
| et.   |                   |            |           |       |      |
| al.   |                   |            |           |       |      |
| 2004. |                   |            |           |       |      |
| This  |                   |            |           |       |      |
| table |                   |            |           |       |      |
| lists |                   |            |           |       |      |
| a     |                   |            |           |       |      |
| c     |                   |            |           |       |      |
| ancer |                   |            |           |       |      |
| risk  |                   |            |           |       |      |
| of    |                   |            |           |       |      |
| 2.9 X |                   |            |           |       |      |
| 1     |                   |            |           |       |      |
| 0^-9^ |                   |            |           |       |      |
| based |                   |            |           |       |      |
| on    |                   |            |           |       |      |
| the   |                   |            |           |       |      |
| H     |                   |            |           |       |      |
| ockey |                   |            |           |       |      |
| stick |                   |            |           |       |      |
| s     |                   |            |           |       |      |
| haped |                   |            |           |       |      |
| CRCP  |                   |            |           |       |      |
| for   |                   |            |           |       |      |
| n     |                   |            |           |       |      |
| on-sm |                   |            |           |       |      |
| okers |                   |            |           |       |      |
| ex    |                   |            |           |       |      |
| posed |                   |            |           |       |      |
| co    |                   |            |           |       |      |
| ntinu |                   |            |           |       |      |
| ously |                   |            |           |       |      |
| 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.

```{=html}
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```
-   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 m^3^ (15,583 ft^3^) 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 ft^2^. This is a standard assumption in the WPEM model.

-   The wallpaper adhesive has a coverage of 200ft^2^/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 ft^2^ for Vinyl over Vinyl Pro-555 to 300 ft^2^/gallon for
    Ultra-Pro-880 Clear Adhesive. The products produced by the Zinnser
    Company also have a similar coverage range which is 230 ft^2^/gallon
    for Suregrip to 280 ft^2^/gallon for Suregrip 122. These values are
    similar to default coverage values used in the WPEM model which is
    200 ft^2/^gallon for primer and 400 ft^2/^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]{.underline}

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-C |                  |              |            |   |      |      |
| ancer |                  |              |            |   |      |      |
| Risks |                  |              |            |   |      |      |
| from  |                  |              |            |   |      |      |
| Daily |                  |              |            |   |      |      |
| E     |                  |              |            |   |      |      |
| xposu |                  |              |            |   |      |      |
| res** |                  |              |            |   |      |      |
+-------+------------------+--------------+------------+---+------+------+
| W     | Amount Used Per  | Exposure     | Peak       |   | MO   |      |
| eight | Day/             | Duration     | Con        |   | E^B^ |      |
| Fra   |                  |              | centration |   |      |      |
| ction | Duration of Use  |              |            |   | (ta  |      |
|       |                  |              |            |   | rget |      |
|       |                  |              |            |   | MOE  |      |
|       |                  |              |            |   | =    |      |
|       |                  |              |            |   | 10)  |      |
+-------+------------------+--------------+------------+---+------+------+
| 0.0   | 2.26             | One day per  | 15 ppb     | 6 |      |      |
| 00037 | gallons/3.42     | event        |            | . |      |      |
|       | hours^A^         |              |            | 7 |      |      |
+-------+------------------+--------------+------------+---+------+------+
| **C   |                  |              |            |   |      |      |
| ancer |                  |              |            |   |      |      |
| Risks |                  |              |            |   |      |      |
| from  |                  |              |            |   |      |      |
| Lif   |                  |              |            |   |      |      |
| etime |                  |              |            |   |      |      |
| E     |                  |              |            |   |      |      |
| xposu |                  |              |            |   |      |      |
| res** |                  |              |            |   |      |      |
+-------+------------------+--------------+------------+---+------+------+
| W     | Amount Used Per  | Exposure     | LADC^C^    | C |      |      |
| eight | Day/             | Frequency    |            | a |      |      |
| Fra   |                  |              |            | n |      |      |
| ction | Duration of Use  |              |            | c |      |      |
|       |                  |              |            | e |      |      |
|       |                  |              |            | r |      |      |
|       |                  |              |            | R |      |      |
|       |                  |              |            | i |      |      |
|       |                  |              |            | s |      |      |
|       |                  |              |            | k |      |      |
+-------+------------------+--------------+------------+---+------+------+
|       |                  |              |            | I |      | CII  |
|       |                  |              |            | R |      | T^E^ |
|       |                  |              |            | I |      |      |
|       |                  |              |            | S |      |      |
|       |                  |              |            | ^ |      |      |
|       |                  |              |            | D |      |      |
|       |                  |              |            | ^ |      |      |
+-------+------------------+--------------+------------+---+------+------+
| 0.0   | 2.26             | 1 day per    | 0.044 ppb  | 7 |      | \<3  |
| 00037 | gallons/3.42     | year         |            | x |      | x    |
|       | hours^A^         |              | (0.053     | 1 |      | 10   |
|       |                  |              | ug/m^3^)   | 0 |      | ^-9^ |
|       |                  |              |            | ^ |      |      |
|       |                  |              |            | - |      |      |
|       |                  |              |            | 7 |      |      |
|       |                  |              |            | ^ |      |      |
+-------+------------------+--------------+------------+---+------+------+
| A.    |                  |              |            |   |      |      |
| High  |                  |              |            |   |      |      |
| end   |                  |              |            |   |      |      |
| de    |                  |              |            |   |      |      |
| fault |                  |              |            |   |      |      |
| a     |                  |              |            |   |      |      |
| ssump |                  |              |            |   |      |      |
| tions |                  |              |            |   |      |      |
| as    |                  |              |            |   |      |      |
| l     |                  |              |            |   |      |      |
| isted |                  |              |            |   |      |      |
| in    |                  |              |            |   |      |      |
| the   |                  |              |            |   |      |      |
| WPEM  |                  |              |            |   |      |      |
| Model |                  |              |            |   |      |      |
| docu  |                  |              |            |   |      |      |
| menta |                  |              |            |   |      |      |
| tion. |                  |              |            |   |      |      |
|       |                  |              |            |   |      |      |
| B.    |                  |              |            |   |      |      |
| MOE = |                  |              |            |   |      |      |
| NOAEL |                  |              |            |   |      |      |
| /Peak |                  |              |            |   |      |      |
| Con   |                  |              |            |   |      |      |
| centr |                  |              |            |   |      |      |
| ation |                  |              |            |   |      |      |
| where |                  |              |            |   |      |      |
| the   |                  |              |            |   |      |      |
| NOAEL |                  |              |            |   |      |      |
| = 0.1 |                  |              |            |   |      |      |
| ppm   |                  |              |            |   |      |      |
| (100  |                  |              |            |   |      |      |
| ppb). |                  |              |            |   |      |      |
|       |                  |              |            |   |      |      |
| C.    |                  |              |            |   |      |      |
| LADC  |                  |              |            |   |      |      |
| =     |                  |              |            |   |      |      |
| Lif   |                  |              |            |   |      |      |
| etime |                  |              |            |   |      |      |
| Av    |                  |              |            |   |      |      |
| erage |                  |              |            |   |      |      |
| Daily |                  |              |            |   |      |      |
| Con   |                  |              |            |   |      |      |
| centr |                  |              |            |   |      |      |
| ation |                  |              |            |   |      |      |
| ass   |                  |              |            |   |      |      |
| uming |                  |              |            |   |      |      |
| exp   |                  |              |            |   |      |      |
| osure |                  |              |            |   |      |      |
| 1 day |                  |              |            |   |      |      |
| per   |                  |              |            |   |      |      |
| year  |                  |              |            |   |      |      |
| and   |                  |              |            |   |      |      |
| 57    |                  |              |            |   |      |      |
| years |                  |              |            |   |      |      |
| per   |                  |              |            |   |      |      |
| 75    |                  |              |            |   |      |      |
| year  |                  |              |            |   |      |      |
| life  |                  |              |            |   |      |      |
| time. |                  |              |            |   |      |      |
|       |                  |              |            |   |      |      |
| D.    |                  |              |            |   |      |      |
| IRIS  |                  |              |            |   |      |      |
| C     |                  |              |            |   |      |      |
| ancer |                  |              |            |   |      |      |
| Risk  |                  |              |            |   |      |      |
| =     |                  |              |            |   |      |      |
| LADC  |                  |              |            |   |      |      |
| \*    |                  |              |            |   |      |      |
| Unit  |                  |              |            |   |      |      |
| Risk  |                  |              |            |   |      |      |
| ,     |                  |              |            |   |      |      |
| where |                  |              |            |   |      |      |
| the   |                  |              |            |   |      |      |
| Unit  |                  |              |            |   |      |      |
| Risk  |                  |              |            |   |      |      |
| is    |                  |              |            |   |      |      |
| 1.3 x |                  |              |            |   |      |      |
| 1     |                  |              |            |   |      |      |
| 0^-5^ |                  |              |            |   |      |      |
| per   |                  |              |            |   |      |      |
| ug    |                  |              |            |   |      |      |
| /m^3^ |                  |              |            |   |      |      |
| as    |                  |              |            |   |      |      |
| l     |                  |              |            |   |      |      |
| isted |                  |              |            |   |      |      |
| in    |                  |              |            |   |      |      |
| IRIS  |                  |              |            |   |      |      |
|       |                  |              |            |   |      |      |
| E.    |                  |              |            |   |      |      |
| CIIT  |                  |              |            |   |      |      |
| C     |                  |              |            |   |      |      |
| ancer |                  |              |            |   |      |      |
| Risk  |                  |              |            |   |      |      |
| is    |                  |              |            |   |      |      |
| taken |                  |              |            |   |      |      |
| from  |                  |              |            |   |      |      |
| Table |                  |              |            |   |      |      |
| 8 of  |                  |              |            |   |      |      |
| Co    |                  |              |            |   |      |      |
| nolly |                  |              |            |   |      |      |
| et.   |                  |              |            |   |      |      |
| al.   |                  |              |            |   |      |      |
| 2004. |                  |              |            |   |      |      |
| This  |                  |              |            |   |      |      |
| table |                  |              |            |   |      |      |
| lists |                  |              |            |   |      |      |
| a     |                  |              |            |   |      |      |
| c     |                  |              |            |   |      |      |
| ancer |                  |              |            |   |      |      |
| risk  |                  |              |            |   |      |      |
| of    |                  |              |            |   |      |      |
| 2.9 X |                  |              |            |   |      |      |
| 1     |                  |              |            |   |      |      |
| 0^-9^ |                  |              |            |   |      |      |
| based |                  |              |            |   |      |      |
| on    |                  |              |            |   |      |      |
| the   |                  |              |            |   |      |      |
| H     |                  |              |            |   |      |      |
| ockey |                  |              |            |   |      |      |
| stick |                  |              |            |   |      |      |
| s     |                  |              |            |   |      |      |
| haped |                  |              |            |   |      |      |
| CRCP  |                  |              |            |   |      |      |
| for   |                  |              |            |   |      |      |
| n     |                  |              |            |   |      |      |
| on-sm |                  |              |            |   |      |      |
| okers |                  |              |            |   |      |      |
| ex    |                  |              |            |   |      |      |
| posed |                  |              |            |   |      |      |
| co    |                  |              |            |   |      |      |
| ntinu |                  |              |            |   |      |      |
| ously |                  |              |            |   |      |      |
| 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 ft^3^ 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 ft^2^.

-   One coat of adhesive which has a coverage of 200 ft^2^/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-C |                  |              |            |      |      |
| ancer |                  |              |            |      |      |
| Risks |                  |              |            |      |      |
| from  |                  |              |            |      |      |
| Daily |                  |              |            |      |      |
| E     |                  |              |            |      |      |
| xposu |                  |              |            |      |      |
| res** |                  |              |            |      |      |
+-------+------------------+--------------+------------+------+------+
| W     | Amount Used Per  | Exposure     | Peak       | MO   |      |
| eight | Day/             | Duration     | Con        | E^B^ |      |
| Fra   |                  |              | centration |      |      |
| ction | Duration of Use  |              |            | (ta  |      |
|       |                  |              |            | rget |      |
|       |                  |              |            | MOE  |      |
|       |                  |              |            | =    |      |
|       |                  |              |            | 10)  |      |
+-------+------------------+--------------+------------+------+------+
| 0.0   | 2.26             | One day per  | 4.9 ppb    | 20   |      |
| 00037 | gallons/3.42     | event        |            |      |      |
|       | hours^A^         |              |            |      |      |
+-------+------------------+--------------+------------+------+------+
| **C   |                  |              |            |      |      |
| ancer |                  |              |            |      |      |
| Risks |                  |              |            |      |      |
| from  |                  |              |            |      |      |
| Lif   |                  |              |            |      |      |
| etime |                  |              |            |      |      |
| E     |                  |              |            |      |      |
| xposu |                  |              |            |      |      |
| res** |                  |              |            |      |      |
+-------+------------------+--------------+------------+------+------+
| W     | Amount Used Per  | Exposure     | LADC^D^    | Ca   |      |
| eight | Day/             | Frequency    |            | ncer |      |
| Fra   |                  |              |            | Risk |      |
| ction | Duration of Use  |              |            |      |      |
+-------+------------------+--------------+------------+------+------+
|       |                  |              |            | IRI  | CII  |
|       |                  |              |            | S^E^ | T^F^ |
+-------+------------------+--------------+------------+------+------+
| 0.0   | 2.26             | 1 day per    | 0.038 ppb  | 6 x  | \<3  |
| 00037 | gallons/3.42     | year         |            | 10   | x    |
|       | hours^A^         |              | (0.047     | ^-7^ | 10   |
|       |                  |              | ug/m^3^)   |      | ^-9^ |
+-------+------------------+--------------+------------+------+------+
| A.    |                  |              |            |      |      |
| High  |                  |              |            |      |      |
| end   |                  |              |            |      |      |
| de    |                  |              |            |      |      |
| fault |                  |              |            |      |      |
| a     |                  |              |            |      |      |
| ssump |                  |              |            |      |      |
| tions |                  |              |            |      |      |
| as    |                  |              |            |      |      |
| l     |                  |              |            |      |      |
| isted |                  |              |            |      |      |
| in    |                  |              |            |      |      |
| the   |                  |              |            |      |      |
| WPEM  |                  |              |            |      |      |
| Model |                  |              |            |      |      |
| docu  |                  |              |            |      |      |
| menta |                  |              |            |      |      |
| tion. |                  |              |            |      |      |
|       |                  |              |            |      |      |
| B.    |                  |              |            |      |      |
| MOE = |                  |              |            |      |      |
| NOAEL |                  |              |            |      |      |
| /Peak |                  |              |            |      |      |
| Con   |                  |              |            |      |      |
| centr |                  |              |            |      |      |
| ation |                  |              |            |      |      |
| where |                  |              |            |      |      |
| the   |                  |              |            |      |      |
| NOAEL |                  |              |            |      |      |
| = 0.1 |                  |              |            |      |      |
| ppm   |                  |              |            |      |      |
| (100  |                  |              |            |      |      |
| ppb). |                  |              |            |      |      |
|       |                  |              |            |      |      |
| C.    |                  |              |            |      |      |
| Lif   |                  |              |            |      |      |
| etime |                  |              |            |      |      |
| Exp   |                  |              |            |      |      |
| osure |                  |              |            |      |      |
| E     |                  |              |            |      |      |
| vents |                  |              |            |      |      |
| =     |                  |              |            |      |      |
| Exp   |                  |              |            |      |      |
| osure |                  |              |            |      |      |
| E     |                  |              |            |      |      |
| vents |                  |              |            |      |      |
| per   |                  |              |            |      |      |
| Year  |                  |              |            |      |      |
| (1.0) |                  |              |            |      |      |
| \*    |                  |              |            |      |      |
| Exp   |                  |              |            |      |      |
| osure |                  |              |            |      |      |
| Years |                  |              |            |      |      |
| per   |                  |              |            |      |      |
| Lif   |                  |              |            |      |      |
| etime |                  |              |            |      |      |
| (57)  |                  |              |            |      |      |
|       |                  |              |            |      |      |
| D.    |                  |              |            |      |      |
| LADC  |                  |              |            |      |      |
| =     |                  |              |            |      |      |
| Lif   |                  |              |            |      |      |
| etime |                  |              |            |      |      |
| Av    |                  |              |            |      |      |
| erage |                  |              |            |      |      |
| Daily |                  |              |            |      |      |
| Con   |                  |              |            |      |      |
| centr |                  |              |            |      |      |
| ation |                  |              |            |      |      |
| ass   |                  |              |            |      |      |
| uming |                  |              |            |      |      |
| exp   |                  |              |            |      |      |
| osure |                  |              |            |      |      |
| 1     |                  |              |            |      |      |
| days  |                  |              |            |      |      |
| per   |                  |              |            |      |      |
| year  |                  |              |            |      |      |
| and   |                  |              |            |      |      |
| 57    |                  |              |            |      |      |
| years |                  |              |            |      |      |
| per   |                  |              |            |      |      |
| 75    |                  |              |            |      |      |
| year  |                  |              |            |      |      |
| life  |                  |              |            |      |      |
| time. |                  |              |            |      |      |
|       |                  |              |            |      |      |
| E.    |                  |              |            |      |      |
| IRIS  |                  |              |            |      |      |
| C     |                  |              |            |      |      |
| ancer |                  |              |            |      |      |
| Risk  |                  |              |            |      |      |
| =     |                  |              |            |      |      |
| LADC  |                  |              |            |      |      |
| \*    |                  |              |            |      |      |
| Unit  |                  |              |            |      |      |
| Risk  |                  |              |            |      |      |
| ,     |                  |              |            |      |      |
| where |                  |              |            |      |      |
| the   |                  |              |            |      |      |
| Unit  |                  |              |            |      |      |
| Risk  |                  |              |            |      |      |
| is    |                  |              |            |      |      |
| 1.3 x |                  |              |            |      |      |
| 1     |                  |              |            |      |      |
| 0^-5^ |                  |              |            |      |      |
| per   |                  |              |            |      |      |
| ug    |                  |              |            |      |      |
| /m^3^ |                  |              |            |      |      |
| as    |                  |              |            |      |      |
| l     |                  |              |            |      |      |
| isted |                  |              |            |      |      |
| in    |                  |              |            |      |      |
| IRIS  |                  |              |            |      |      |
|       |                  |              |            |      |      |
| F.    |                  |              |            |      |      |
| CIIT  |                  |              |            |      |      |
| C     |                  |              |            |      |      |
| ancer |                  |              |            |      |      |
| Risk  |                  |              |            |      |      |
| is    |                  |              |            |      |      |
| taken |                  |              |            |      |      |
| from  |                  |              |            |      |      |
| Table |                  |              |            |      |      |
| 8 of  |                  |              |            |      |      |
| Co    |                  |              |            |      |      |
| nolly |                  |              |            |      |      |
| et.   |                  |              |            |      |      |
| al.   |                  |              |            |      |      |
| 2004. |                  |              |            |      |      |
| This  |                  |              |            |      |      |
| table |                  |              |            |      |      |
| lists |                  |              |            |      |      |
| a     |                  |              |            |      |      |
| c     |                  |              |            |      |      |
| ancer |                  |              |            |      |      |
| risk  |                  |              |            |      |      |
| of    |                  |              |            |      |      |
| 2.9 X |                  |              |            |      |      |
| 1     |                  |              |            |      |      |
| 0^-9^ |                  |              |            |      |      |
| based |                  |              |            |      |      |
| on    |                  |              |            |      |      |
| the   |                  |              |            |      |      |
| H     |                  |              |            |      |      |
| ockey |                  |              |            |      |      |
| stick |                  |              |            |      |      |
| s     |                  |              |            |      |      |
| haped |                  |              |            |      |      |
| CRCP  |                  |              |            |      |      |
| for   |                  |              |            |      |      |
| n     |                  |              |            |      |      |
| on-sm |                  |              |            |      |      |
| okers |                  |              |            |      |      |
| ex    |                  |              |            |      |      |
| posed |                  |              |            |      |      |
| co    |                  |              |            |      |      |
| ntinu |                  |              |            |      |      |
| ously |                  |              |            |      |      |
| 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]{.underline}

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  |          |          |           |         |   |       |       |
| Expos  |          |          |           |         |   |       |       |
| ures** |          |          |           |         |   |       |       |
+--------+----------+----------+-----------+---------+---+-------+-------+
| Weight | Amount   | Duration | Duration  | Peak    |   | M     |       |
| Fr     | of       | of Use   | of        | Concen  |   | OE^B^ |       |
| action | Product  |          | Exposure  | tration |   |       |       |
|        | Used     |          |           |         |   | (t    |       |
|        |          |          |           |         |   | arget |       |
|        |          |          |           |         |   | MOE = |       |
|        |          |          |           |         |   | 10)   |       |
+--------+----------+----------+-----------+---------+---+-------+-------+
| 0.91   | 113.4    | 720      | 1 day     | 78,000  | \ |       |       |
|        | grams    | hours^A^ |           | ppb     | < |       |       |
|        |          |          |           |         | 0 |       |       |
|        |          |          |           |         | . |       |       |
|        |          |          |           |         | 1 |       |       |
+--------+----------+----------+-----------+---------+---+-------+-------+
| **     |          |          |           |         |   |       |       |
| Cancer |          |          |           |         |   |       |       |
| Risks  |          |          |           |         |   |       |       |
| from   |          |          |           |         |   |       |       |
| Li     |          |          |           |         |   |       |       |
| fetime |          |          |           |         |   |       |       |
| Expos  |          |          |           |         |   |       |       |
| ures** |          |          |           |         |   |       |       |
+--------+----------+----------+-----------+---------+---+-------+-------+
| Weight | Amount   | Duration | Frequency | LADC^C^ | C |       |       |
| Fr     | of       | of Use   | of Use    |         | a |       |       |
| action | Product  |          | per Year  |         | n |       |       |
|        | Used     |          |           |         | c |       |       |
|        |          |          |           |         | e |       |       |
|        |          |          |           |         | r |       |       |
|        |          |          |           |         | R |       |       |
|        |          |          |           |         | i |       |       |
|        |          |          |           |         | s |       |       |
|        |          |          |           |         | k |       |       |
+--------+----------+----------+-----------+---------+---+-------+-------+
|        |          |          |           |         | I |       | CI    |
|        |          |          |           |         | R |       | IT^E^ |
|        |          |          |           |         | I |       |       |
|        |          |          |           |         | S |       |       |
|        |          |          |           |         | ^ |       |       |
|        |          |          |           |         | D |       |       |
|        |          |          |           |         | ^ |       |       |
+--------+----------+----------+-----------+---------+---+-------+-------+
| 0.91   | 113.4    | 720      | 6.12      | 170 ppb | 3 |       | \<8 x |
|        | grams    | hours^A^ | times     |         | x |       | 1     |
|        |          |          |           | (210    | 1 |       | 0^-7^ |
|        |          |          |           | u       | 0 |       |       |
|        |          |          |           | g/m^3^) | ^ |       |       |
|        |          |          |           |         | - |       |       |
|        |          |          |           |         | 3 |       |       |
|        |          |          |           |         | ^ |       |       |
+--------+----------+----------+-----------+---------+---+-------+-------+
| A.     |          |          |           |         |   |       |       |
| C      |          |          |           |         |   |       |       |
| entral |          |          |           |         |   |       |       |
| te     |          |          |           |         |   |       |       |
| ndency |          |          |           |         |   |       |       |
| d      |          |          |           |         |   |       |       |
| efault |          |          |           |         |   |       |       |
| assum  |          |          |           |         |   |       |       |
| ptions |          |          |           |         |   |       |       |
| as     |          |          |           |         |   |       |       |
| listed |          |          |           |         |   |       |       |
| in the |          |          |           |         |   |       |       |
| CEM    |          |          |           |         |   |       |       |
| Model  |          |          |           |         |   |       |       |
| do     |          |          |           |         |   |       |       |
| cument |          |          |           |         |   |       |       |
| ation. |          |          |           |         |   |       |       |
|        |          |          |           |         |   |       |       |
| B. MOE |          |          |           |         |   |       |       |
| =      |          |          |           |         |   |       |       |
| NOAE   |          |          |           |         |   |       |       |
| L/Peak |          |          |           |         |   |       |       |
| C      |          |          |           |         |   |       |       |
| oncent |          |          |           |         |   |       |       |
| ration |          |          |           |         |   |       |       |
| where  |          |          |           |         |   |       |       |
| the    |          |          |           |         |   |       |       |
| NOAEL  |          |          |           |         |   |       |       |
| = 0.1  |          |          |           |         |   |       |       |
| ppm    |          |          |           |         |   |       |       |
| (100   |          |          |           |         |   |       |       |
| ppb).  |          |          |           |         |   |       |       |
|        |          |          |           |         |   |       |       |
| C.     |          |          |           |         |   |       |       |
| LADC = |          |          |           |         |   |       |       |
| Li     |          |          |           |         |   |       |       |
| fetime |          |          |           |         |   |       |       |
| A      |          |          |           |         |   |       |       |
| verage |          |          |           |         |   |       |       |
| Daily  |          |          |           |         |   |       |       |
| C      |          |          |           |         |   |       |       |
| oncent |          |          |           |         |   |       |       |
| ration |          |          |           |         |   |       |       |
|        |          |          |           |         |   |       |       |
| D.     |          |          |           |         |   |       |       |
| IRIS   |          |          |           |         |   |       |       |
| Cancer |          |          |           |         |   |       |       |
| Risk = |          |          |           |         |   |       |       |
| LADC   |          |          |           |         |   |       |       |
| \*     |          |          |           |         |   |       |       |
| Unit   |          |          |           |         |   |       |       |
| Risk , |          |          |           |         |   |       |       |
| where  |          |          |           |         |   |       |       |
| the    |          |          |           |         |   |       |       |
| Unit   |          |          |           |         |   |       |       |
| Risk   |          |          |           |         |   |       |       |
| is 1.3 |          |          |           |         |   |       |       |
| x      |          |          |           |         |   |       |       |
| 10^-5^ |          |          |           |         |   |       |       |
| per    |          |          |           |         |   |       |       |
| u      |          |          |           |         |   |       |       |
| g/m^3^ |          |          |           |         |   |       |       |
| as     |          |          |           |         |   |       |       |
| listed |          |          |           |         |   |       |       |
| in     |          |          |           |         |   |       |       |
| IRIS   |          |          |           |         |   |       |       |
|        |          |          |           |         |   |       |       |
| E.     |          |          |           |         |   |       |       |
| CIIT   |          |          |           |         |   |       |       |
| Cancer |          |          |           |         |   |       |       |
| Risk   |          |          |           |         |   |       |       |
| is     |          |          |           |         |   |       |       |
| taken  |          |          |           |         |   |       |       |
| from   |          |          |           |         |   |       |       |
| Table  |          |          |           |         |   |       |       |
| 8 of   |          |          |           |         |   |       |       |
| C      |          |          |           |         |   |       |       |
| onolly |          |          |           |         |   |       |       |
| et.    |          |          |           |         |   |       |       |
| al.    |          |          |           |         |   |       |       |
| 2004.  |          |          |           |         |   |       |       |
| This   |          |          |           |         |   |       |       |
| table  |          |          |           |         |   |       |       |
| lists  |          |          |           |         |   |       |       |
| a      |          |          |           |         |   |       |       |
| cancer |          |          |           |         |   |       |       |
| risk   |          |          |           |         |   |       |       |
| of 7.5 |          |          |           |         |   |       |       |
| X      |          |          |           |         |   |       |       |
| 10^-7^ |          |          |           |         |   |       |       |
| based  |          |          |           |         |   |       |       |
| on the |          |          |           |         |   |       |       |
| Hockey |          |          |           |         |   |       |       |
| stick  |          |          |           |         |   |       |       |
| shaped |          |          |           |         |   |       |       |
| CRCP   |          |          |           |         |   |       |       |
| for    |          |          |           |         |   |       |       |
| non-s  |          |          |           |         |   |       |       |
| mokers |          |          |           |         |   |       |       |
| e      |          |          |           |         |   |       |       |
| xposed |          |          |           |         |   |       |       |
| contin |          |          |           |         |   |       |       |
| uously |          |          |           |         |   |       |       |
| 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 | **MOE**      | **L   | **Ca |      |
|                 | Conce      |              | ADC** | ncer |      |
|                 | ntration** | **(Target    |       | Ri   |      |
|                 |            | MOE =10)**   |       | sk** |      |
+-----------------+------------+--------------+-------+------+------+
|                 |            |              |       | **IR | **CI |
|                 |            |              |       | IS** | IT** |
+-----------------+------------+--------------+-------+------+------+
| Laundry         | 240 ppb    | 0.4          | 0.5   | 8 x  | \<3  |
| Detergent       |            |              | ppb   | 10   | x    |
| Handler         |            |              |       | ^-6^ | 10   |
|                 |            |              |       |      | ^-9^ |
+-----------------+------------+--------------+-------+------+------+
| General Purpose | 21 ppb     | 4.8          | 0.12  | 2 x  | \<3  |
| Cleaner Handler |            |              | ppb   | 10   | x    |
|                 |            |              |       | ^-6^ | 10   |
|                 |            |              |       |      | ^-9^ |
+-----------------+------------+--------------+-------+------+------+
| Wall Paper      | 15 ppb     | 6.7          | 0.044 | 7 x  | \<3  |
| Adhesive        |            |              | ppb   | 10   | x    |
| Handler         |            |              |       | ^-7^ | 10   |
|                 |            |              |       |      | ^-9^ |
+-----------------+------------+--------------+-------+------+------+
| Wall Paper      | 4.9 ppb    | 20           | 0.038 | 6 x  | \<3  |
| Adhesive        |            |              | ppb   | 10   | x    |
|                 |            |              |       | ^-7^ | 10   |
| Post            |            |              |       |      | ^-9^ |
| Application     |            |              |       |      |      |
+-----------------+------------+--------------+-------+------+------+

[Paraformaldehyde]{.underline}

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.

[]{#__RefHeading___Toc195349019 .anchor}**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.

[]{#__RefHeading___Toc195349020 .anchor}**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 formaldehyde/parfaformaldehyde. 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
[[http://www.epa.gov/pesticides/cumulative/]{.underline}](http://www.epa.gov/pesticides/cumulative/_).

[]{#__RefHeading___Toc195349021 .anchor}**7.0 OCCUPATIONAL EXPOSURE
ASSESSMENT**

[]{#__RefHeading___Toc195349022 .anchor}**7.1** **Occupational Handler
Exposures**

[Occupational Handler Scenarios]{.underline}

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]{.underline}

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^-4^mm 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]{.underline}

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]{.underline}

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]{.underline}

Catalyzed fumigation is similar to evaporative fumigation with the
exception that potassium permanganate (KMnO~4~) is added to catalyze the
release of formaldehyde gas. The application rate is 16.6 ounces of
KMnO~4~ and 20 ounces of formaldehyde per 1000 cubic feet. The
application is made by pouring the formaldehyde solution into a small
pan containing KMnO~4~ 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]{.underline}

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 ft^3^ (based on an 8 foot
sidewall and a four foot roof peak) then the maximum theoretical
formaldehyde concentration would be 18 mg/m^3^ (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]{.underline}

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]{.underline}

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]{.underline}

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.

```{=html}
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```
-   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 ft^3^ which is the mean value from the Exposure Factors
    Handbook (US EPA, 1997).

-   The surface area papered is 2131 ft^2^.

-   One coat of adhesive which has a coverage of 200 ft^2^/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]{.underline}

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-C |                   |            |            |      |      |
| ancer |                   |            |            |      |      |
| Risks |                   |            |            |      |      |
| from  |                   |            |            |      |      |
| Daily |                   |            |            |      |      |
| E     |                   |            |            |      |      |
| xposu |                   |            |            |      |      |
| res** |                   |            |            |      |      |
+-------+-------------------+------------+------------+------+------+
| W     | Amount Used Per   | Exposure   | Peak       | MO   |      |
| eight | Day/              | Duration   | Con        | E^B^ |      |
| Fra   |                   |            | centration |      |      |
| ction | Duration of Use   |            |            |      |      |
+-------+-------------------+------------+------------+------+------+
| 0.0   | 10.66 gallons/6.3 | One day    | 63 ppb     | 1.6  |      |
| 00037 | hours^A^          | per event  |            |      |      |
+-------+-------------------+------------+------------+------+------+
| **C   |                   |            |            |      |      |
| ancer |                   |            |            |      |      |
| Risks |                   |            |            |      |      |
| from  |                   |            |            |      |      |
| Lif   |                   |            |            |      |      |
| etime |                   |            |            |      |      |
| E     |                   |            |            |      |      |
| xposu |                   |            |            |      |      |
| res** |                   |            |            |      |      |
+-------+-------------------+------------+------------+------+------+
| W     | Amount Used Per   | Lifetime   | LADC^D^    | Ca   |      |
| eight | Day/              | Exposure   |            | ncer |      |
| Fra   |                   | Events^C^  |            | Risk |      |
| ction | Duration of Use   |            |            |      |      |
+-------+-------------------+------------+------------+------+------+
|       |                   |            |            | IRI  | CII  |
|       |                   |            |            | S^E^ | T^F^ |
+-------+-------------------+------------+------------+------+------+
| 0.0   | 10.66 gallons/6.3 | 8400       | 3.5 ppb    | 6 x  | \<1  |
| 00037 | hours^A^          |            |            | 10   | x    |
|       |                   |            | (4.2       | ^-5^ | 10   |
|       |                   |            | ug/m^3^)   |      | ^-8^ |
+-------+-------------------+------------+------------+------+------+
| A.    |                   |            |            |      |      |
| High  |                   |            |            |      |      |
| end   |                   |            |            |      |      |
| de    |                   |            |            |      |      |
| fault |                   |            |            |      |      |
| a     |                   |            |            |      |      |
| ssump |                   |            |            |      |      |
| tions |                   |            |            |      |      |
| as    |                   |            |            |      |      |
| l     |                   |            |            |      |      |
| isted |                   |            |            |      |      |
| in    |                   |            |            |      |      |
| the   |                   |            |            |      |      |
| WPEM  |                   |            |            |      |      |
| Model |                   |            |            |      |      |
| docu  |                   |            |            |      |      |
| menta |                   |            |            |      |      |
| tion. |                   |            |            |      |      |
|       |                   |            |            |      |      |
| B.    |                   |            |            |      |      |
| MOE = |                   |            |            |      |      |
| NOAEL |                   |            |            |      |      |
| /Peak |                   |            |            |      |      |
| Con   |                   |            |            |      |      |
| centr |                   |            |            |      |      |
| ation |                   |            |            |      |      |
| where |                   |            |            |      |      |
| the   |                   |            |            |      |      |
| NOAEL |                   |            |            |      |      |
| = 0.1 |                   |            |            |      |      |
| ppm   |                   |            |            |      |      |
| (100  |                   |            |            |      |      |
| ppb). |                   |            |            |      |      |
|       |                   |            |            |      |      |
| C.    |                   |            |            |      |      |
| Lif   |                   |            |            |      |      |
| etime |                   |            |            |      |      |
| Exp   |                   |            |            |      |      |
| osure |                   |            |            |      |      |
| E     |                   |            |            |      |      |
| vents |                   |            |            |      |      |
| =     |                   |            |            |      |      |
| Exp   |                   |            |            |      |      |
| osure |                   |            |            |      |      |
| E     |                   |            |            |      |      |
| vents |                   |            |            |      |      |
| per   |                   |            |            |      |      |
| Year  |                   |            |            |      |      |
| (240) |                   |            |            |      |      |
| \*    |                   |            |            |      |      |
| Exp   |                   |            |            |      |      |
| osure |                   |            |            |      |      |
| Years |                   |            |            |      |      |
| per   |                   |            |            |      |      |
| Lif   |                   |            |            |      |      |
| etime |                   |            |            |      |      |
| (35)  |                   |            |            |      |      |
|       |                   |            |            |      |      |
| D.    |                   |            |            |      |      |
| LADC  |                   |            |            |      |      |
| =     |                   |            |            |      |      |
| Lif   |                   |            |            |      |      |
| etime |                   |            |            |      |      |
| Av    |                   |            |            |      |      |
| erage |                   |            |            |      |      |
| Daily |                   |            |            |      |      |
| Con   |                   |            |            |      |      |
| centr |                   |            |            |      |      |
| ation |                   |            |            |      |      |
|       |                   |            |            |      |      |
| E.    |                   |            |            |      |      |
| IRIS  |                   |            |            |      |      |
| C     |                   |            |            |      |      |
| ancer |                   |            |            |      |      |
| Risk  |                   |            |            |      |      |
| =     |                   |            |            |      |      |
| LADC  |                   |            |            |      |      |
| \*    |                   |            |            |      |      |
| Unit  |                   |            |            |      |      |
| Risk  |                   |            |            |      |      |
| ,     |                   |            |            |      |      |
| where |                   |            |            |      |      |
| the   |                   |            |            |      |      |
| Unit  |                   |            |            |      |      |
| Risk  |                   |            |            |      |      |
| is    |                   |            |            |      |      |
| 1.3 x |                   |            |            |      |      |
| 1     |                   |            |            |      |      |
| 0^-5^ |                   |            |            |      |      |
| per   |                   |            |            |      |      |
| ug    |                   |            |            |      |      |
| /m^3^ |                   |            |            |      |      |
| as    |                   |            |            |      |      |
| l     |                   |            |            |      |      |
| isted |                   |            |            |      |      |
| in    |                   |            |            |      |      |
| IRIS  |                   |            |            |      |      |
|       |                   |            |            |      |      |
| F.    |                   |            |            |      |      |
| CIIT  |                   |            |            |      |      |
| C     |                   |            |            |      |      |
| ancer |                   |            |            |      |      |
| Risk  |                   |            |            |      |      |
| is    |                   |            |            |      |      |
| taken |                   |            |            |      |      |
| from  |                   |            |            |      |      |
| Table |                   |            |            |      |      |
| 8 of  |                   |            |            |      |      |
| Co    |                   |            |            |      |      |
| nolly |                   |            |            |      |      |
| et.   |                   |            |            |      |      |
| al.   |                   |            |            |      |      |
| 2004. |                   |            |            |      |      |
| This  |                   |            |            |      |      |
| table |                   |            |            |      |      |
| lists |                   |            |            |      |      |
| a     |                   |            |            |      |      |
| c     |                   |            |            |      |      |
| ancer |                   |            |            |      |      |
| risk  |                   |            |            |      |      |
| of    |                   |            |            |      |      |
| 1.45  |                   |            |            |      |      |
| X     |                   |            |            |      |      |
| 1     |                   |            |            |      |      |
| 0^-8^ |                   |            |            |      |      |
| for   |                   |            |            |      |      |
| oc    |                   |            |            |      |      |
| cupat |                   |            |            |      |      |
| ional |                   |            |            |      |      |
| expo  |                   |            |            |      |      |
| sures |                   |            |            |      |      |
| at    |                   |            |            |      |      |
| 0.01  |                   |            |            |      |      |
| ppm   |                   |            |            |      |      |
| (     |                   |            |            |      |      |
| Light |                   |            |            |      |      |
| work, |                   |            |            |      |      |
| H     |                   |            |            |      |      |
| ockey |                   |            |            |      |      |
| stick |                   |            |            |      |      |
| CRCP, |                   |            |            |      |      |
| no    |                   |            |            |      |      |
| nsmok |                   |            |            |      |      |
| ing). |                   |            |            |      |      |
+-------+-------------------+------------+------------+------+------+

[]{#__RefHeading___Toc195349023 .anchor}**7.2** **Occupational Handler
Risk Summary and Characterization**

[Non-Cancer Risks]{.underline}

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]{.underline}

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/m^3^(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      | **Average Daily  | **Lifetime       | **Ca |       |
| Daily          | Concentration at | Average Daily    | ncer |       |
| Concentration  | Work and at      | Co               | Ri   |       |
| at Work**      | Home^A^**        | ncentration^B^** | sk** |       |
|                |                  |                  |      |       |
| **(8 hour      | **(24 hour       |                  |      |       |
| TWA)**         | TWA)**           |                  |      |       |
+----------------+------------------+------------------+------+-------+
|                |                  |                  | **I  | *     |
|                |                  |                  | RIS^ | *CIIT |
|                |                  |                  | C^** | ^D^** |
+----------------+------------------+------------------+------+-------+
| 0.03 ppm       | 0.01 ppm         | 4.5 ug/m^3^      | 6 x  | \<1 x |
|                |                  |                  | 10   | 1     |
| (41 ug/m^3^)   | (13.7 ug/m^3^)   | (3.7 ppb)        | ^-5^ | 0^-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/m^3^ 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]{.underline}

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.

[]{#__RefHeading___Toc195349024 .anchor}**7.3 Occupational
Post-application Exposures**

[Formaldehyde]{.underline}

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 (ft^3^) 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 ft^3^
    based upon the following:

> (60 fluid oz applied per 1000 ft^3^ / 128 fluid oz per gallon) x (9.0
> lb per gallon \* 37% a.i.)

-   The initial concentration is 25,000 mg/m^3^ based upon the
    following:

> (1.56 lb a.i. \* 454,000 mg per lb) / (1000 ft^3^ \* 0.0283 m^3^ per
> ft^3^)

-   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.

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-   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 | **Air       | **Relevant Standard**           |
| Ventilation          | Conc        |                                 |
| Activation           | entration** | **(ppm)**                       |
| (minutes)**          |             |                                 |
|                      | **(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]{.underline}

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.

[]{#__RefHeading___Toc195349025 .anchor}**8.0 HUMAN HEALTH RISK
MITIGATION RECOMMENDATIONS**

[Formaldehyde Residential Risks]{.underline}

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

                                             **CIIT**   **IRIS**   

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

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

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

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

[Formaldehyde Occupational Risks]{.underline}

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.

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-   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]{.underline}

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.

[]{#__RefHeading___Toc195349026 .anchor}**9.0 ENVIRONMENTAL RISKS**

[]{#__RefHeading___Toc195349027 .anchor}**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**

+-----------+------------+-----------+-------+---------------+--------+
| **        | **C        | **E       | **Tox | **Satisfies   | *      |
| Species** | hemical,** | ndpoint** | icity | Guidelines/** | *Refer |
|           |            |           | Categ |               | ence** |
|           | **%        | **(ppm)** | ory** | **Comments**  |        |
|           | (a.i.)**   |           |       |               | **(M   |
|           |            |           |       |               | RID)** |
|           | **Tested** |           |       |               |        |
+-----------+------------+-----------+-------+---------------+--------+
| Bobwhite  | Fo         | LD~50~ =  | Sli   | **Yes/core    | 00     |
| quail     | rmaldehyde | 790       | ghtly | study**       | 148774 |
|           |            |           | toxic |               |        |
| (*Colinus | 37%        | NOAEL =   |       | \- 21-day     |        |
| virg      |            | 464       |       | test duration |        |
| inianus*) | (as        |           |       |               |        |
|           | Su         |           |       |               |        |
|           | rflo-B315) |           |       |               |        |
+-----------+------------+-----------+-------+---------------+--------+

[Formaldehyde]{.underline}:

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]{.underline}**:**

No studies are available.

[CONCLUSIONS]{.underline}:

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

+-----------+------------+--------+--------+---------------+--------+
| **        | **C        | **Endp | **To   | **Satisfies   | *      |
| Species** | hemical,** | oint** | xicity | Guidelines/** | *Refer |
|           |            |        | Cate   |               | ence** |
|           | **% a.i.   | **(    | gory** | **Comments**  |        |
|           | Tested**   | ppm)** |        |               | **(M   |
|           |            |        |        |               | RID)** |
+-----------+------------+--------+--------+---------------+--------+
| Bobwhite  | Fo         | LC~50~ | Pract  | **Yes/core    | 00     |
| quail     | rmaldehyde | (diet) | ically | study**       | 148773 |
|           | 37%        | =      | no     |               |        |
| (*Colinus |            | \>5000 | ntoxic | \- 8-day test |        |
| virg      | (as        |        |        | duration      |        |
| inianus)* | Su         |        |        |               |        |
|           | rflo-B315) |        |        |               |        |
+-----------+------------+--------+--------+---------------+--------+
| Mallard   | Fo         | LC~50~ | Pract  | **Yes/core    | 00     |
| duck      | rmaldehyde | (diet) | ically | study**       | 148775 |
|           |            | \>     | no     |               |        |
| (*Anas    | 37%        | 5000   | ntoxic | \- 8-day test |        |
| platyr    |            |        |        | duration      |        |
| hynchos*) | (as        |        |        |               |        |
|           | Su         |        |        |               |        |
|           | rflo-B315) |        |        |               |        |
+-----------+------------+--------+--------+---------------+--------+

[Formaldehyde]{.underline}:

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]{.underline}:

No studies are available.

[CONCLUSIONS]{.underline}:

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

+-----------+-------------+---------+--------+---------------+--------+
| **        | **          | **End   | **To   | **Satisfies   | *      |
| Species** | Chemical,** | point** | xicity | Guidelines/** | *Refer |
|           |             |         | Cate   |               | ence** |
|           | **% a.i.    | **      | gory** | **Comments**  |        |
|           | Tested**    | (ppm)** |        |               | **(M   |
|           |             |         |        |               | RID)** |
+===========+=============+=========+========+===============+========+
| Rainbow   | F           | LC~50~  | Pract  | **Yes/core    | 00     |
| trout     | ormaldehyde | = 118   | ically | study**       | 132485 |
| (O*nc     |             |         | no     |               |        |
| orhynchus | 37%         | NOAEC = | ntoxic | \- 96-hr test |        |
| mykiss*)  |             | 70      |        | duration      |        |
|           |             |         |        |               |        |
|           |             |         |        | \- static     |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Rainbow   | F           | LC~50~  | Sl     | **No          | 00     |
| trout     | ormaldehyde | = 73.3  | ightly | /supplemental | 101857 |
| (O*nc     | 25.9%       |         | toxic  | study**       |        |
| orhynchus |             | (a.i.)  |        |               |        |
| mykiss*)  | (as         |         |        | \- 96-hr test |        |
|           | Surflo-B16) |         |        | duration      |        |
|           |             |         |        |               |        |
|           |             |         |        | \- static     |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Rainbow   | F           | LC~50~  | Mode   | **No          | 00     |
| trout     | ormaldehyde | = 2.24  | rately | /supplemental | 101857 |
| (O*nc     | 32.37%      |         | toxic  | study**       |        |
| orhynchus |             | (a.i.)  |        |               |        |
| mykiss*)  | (as         |         |        | \- 96-hr test |        |
|           | Surflo-B17) |         |        | duration      |        |
|           |             |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Rainbow   | F           | LC~50~  | Mode   | **No          | 00     |
| trout     | ormaldehyde | = 1.41  | rately | /supplemental | 101857 |
| (O*nc     |             |         | toxic  | study**       |        |
| orhynchus | 27.75%      | (a.i.)  |        |               |        |
| mykiss*)  |             |         |        | \- 96-hr test |        |
|           | (as         |         |        | duration      |        |
|           | Surflo-B19) |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Rainbow   | F           | LC~50~  | Pract  | **No/         | 00     |
| trout     | ormaldehyde | \> 100  | ically | supplemental  | 134124 |
| (O*nc     |             |         | no     | study**       |        |
| orhynchus | 18.8%       |         | ntoxic |               |        |
| mykiss*)  |             |         |        | \- - 96-hr    |        |
|           | (as         |         |        | test duration |        |
|           | Russell's   |         |        |               |        |
|           | Incubator   |         |        | \- - static   |        |
|           | Fumigant)   |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Bluegill  | F           | LC~50~  | Sl     | **Yes/core    | 00     |
| sunfish   | ormaldehyde | = 100   | ightly | study**       | 132485 |
|           |             |         | toxic  |               |        |
| (*Lepomis | 37%         | NOAEC = |        | \- - 96-hr    |        |
| macr      |             | 50      |        | test duration |        |
| ochirus*) |             |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Bluegill  | F           | LC~50~  | Sl     | **No          | 00     |
| sunfish   | ormaldehyde | = 41.4  | ightly | /supplemental | 101857 |
|           | 25.9%       |         | toxic  | study**       |        |
| (*Lepomis |             |         |        |               |        |
| macr      | (as         |         |        | \- - 96-hr    |        |
| ochirus*) | Surflo-B16) |         |        | test duration |        |
|           |             |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Bluegill  | F           | LC~50~  | Mode   | **No          | 00     |
| sunfish   | ormaldehyde | = 1.79  | rately | /supplemental | 101857 |
|           | 32.37%      |         | toxic  | study**       |        |
| (*Lepomis |             |         |        |               |        |
| macr      | (as         |         |        | \- - 96-hr    |        |
| ochirus*) | Surflo-B17) |         |        | test duration |        |
|           |             |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Bluegill  | F           | LC~50~  | Mode   | **No          | 00     |
| sunfish   | ormaldehyde | = 1.51  | rately | /supplemental | 101857 |
|           |             |         | toxic  | study**       |        |
| (*Lepomis | 27.75%      |         |        |               |        |
| macr      |             |         |        | \- - 96-hr    |        |
| ochirus*) | (as         |         |        | test duration |        |
|           | Surflo-B19) |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Bluegill  | F           | LC~50~  | Sl     | **No          | 00     |
| sunfish   | ormaldehyde | = 68    | ightly | /supplemental | 134126 |
| (*Lepomis |             |         | toxic  | study**       |        |
| macr      | 37%         |         |        |               |        |
| ochirus)* |             |         |        | \- - 96-hr    |        |
|           | (as         |         |        | test duration |        |
|           | Parson's    |         |        |               |        |
|           | Fo          |         |        | \- static     |        |
|           | rmaldehyde) |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Bluegill  | F           | LC~50~  | Pract  | **No          | 00     |
| sunfish   | ormaldehyde | \> 118  | ically | /supplemental | 134123 |
| (*Lepomis | 8.8%        |         | no     | study**       |        |
| macr      |             |         | ntoxic |               |        |
| ochirus)* | (as         |         |        | \- 96-hr test |        |
|           | Russell's   |         |        | duration      |        |
|           | Incubator   |         |        |               |        |
|           | Fumigant)   |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Atlantic  | F           | LC~50~  | Pract  | **No          | 00     |
| salmon    | ormaldehyde | = 173   | ically | /supplemental | 132485 |
|           |             |         | no     | study**       |        |
| *(Salmo   | 37%         |         | ntoxic |               |        |
| salar)*   |             |         |        | \- - 96-hr    |        |
|           |             |         |        | test duration |        |
|           |             |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Lake      | F           | LC~50~  | Sl     | **No          | 00     |
| trout     | ormaldehyde | = 100   | ightly | /supplemental | 132485 |
|           |             |         | toxic  | study**       |        |
| *(S       | 37%         |         |        |               |        |
| alvelinus |             |         |        | \- - 96-hr    |        |
| na        |             |         |        | test duration |        |
| maycush)* |             |         |        |               |        |
|           |             |         |        | \- - static   |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Black     | F           | LC~50~  | Sl     | **No          | 00     |
| bullhead  | ormaldehyde | = 62.1  | ightly | /supplemental | 132485 |
|           |             |         | toxic  | study**       |        |
| *         | 37%         |         |        |               |        |
| (Ameiurus |             |         |        | \- - 96-hr    |        |
| melas)*   |             |         |        | test duration |        |
|           |             |         |        |               |        |
|           |             |         |        | \- static     |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Channel   | F           | LC~50~  | Sl     | **No          | 00     |
| catfish   | ormaldehyde | = 65.8  | ightly | /supplemental | 132485 |
|           |             |         | toxic  | study**       |        |
| *(        | 37%         |         |        |               |        |
| Ictalurus |             |         |        | \- - 96-hr    |        |
| pu        |             |         |        | test duration |        |
| nctatus)* |             |         |        |               |        |
|           |             |         |        | \- static     |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| Green     | F           | LC~50~  | Pract  | **No          | 00     |
| sunfish   | ormaldehyde | = 173   | ically | /supplemental | 132485 |
|           |             |         | no     | study**       |        |
| *(Lepomis | 37%         |         | ntoxic |               |        |
| cy        |             |         |        | \- - 96-hr    |        |
| anellus)* |             |         |        | test duration |        |
|           |             |         |        |               |        |
|           |             |         |        | \- static     |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| S         | F           | LC~50~  | Pract  | **No          | 00     |
| mallmouth | ormaldehyde | = 136   | ically | /supplemental | 132485 |
| bass      |             |         | no     | study**       |        |
|           | 37%         |         | ntoxic |               |        |
| *(Mi      |             |         |        | \- - 96-hr    |        |
| cropterus |             |         |        | test duration |        |
| d         |             |         |        |               |        |
| olomieu)* |             |         |        | \- static     |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+
| L         | F           | LC~50~  | Pract  | **No          | 00     |
| argemouth | ormaldehyde | = 143   | ically | /supplemental | 132485 |
| bass      |             |         | no     | study**       |        |
|           | 37%         |         | ntoxic |               |        |
| *(Mi      |             |         |        | \- - 96-hr    |        |
| cropterus |             |         |        | test duration |        |
| sa        |             |         |        |               |        |
| lmoides)* |             |         |        | \- static     |        |
|           |             |         |        | test system   |        |
+-----------+-------------+---------+--------+---------------+--------+

# 

**Table 9.4. Acute Toxicity of Paraformaldehyde to Freshwater Fish**

+-----------+------------+----------+--------+---------------+--------+
| **        | **C        | **En     | **To   | **Satisfies   | *      |
| Species** | hemical,** | dpoint** | xicity | Guidelines/** | *Refer |
|           |            |          | Cate   |               | ence** |
|           | **%        | *        | gory** | **Comments**  |        |
|           | (a.i.)**   | *(ppm)** |        |               | **(M   |
|           |            |          |        |               | RID)** |
|           | **Tested** |          |        |               |        |
+===========+============+==========+========+===============+========+
| Rainbow   | Parafo     | LC~50~ = | Sl     | **No          | 00     |
| trout     | rmaldehyde | 51.2     | ightly | /supplemental | 101865 |
| (O*nc     |            | (a.i.)   | toxic  | study**       |        |
| orhynchus | 91%        |          |        |               |        |
| mykiss*)  |            | NOAEC =  |        | \- - 96-hr    |        |
|           | (as        | 32       |        | test duration |        |
|           | Aldacide)  | (a.i.)   |        |               |        |
|           |            |          |        | \- - static   |        |
|           |            |          |        | test system   |        |
+-----------+------------+----------+--------+---------------+--------+
| Bluegill  | Parafo     | LC~50~ = | Sl     | **No          | 00     |
| sunfish   | rmaldehyde | 39.1     | ightly | /supplemental | 101865 |
|           |            |          | toxic  | study**       |        |
| (*Lepomis | 91%        | NOAEC =  |        |               |        |
| macr      |            | 32       |        | \- - 96-hr    |        |
| ochirus*) | (as        | (a.i.)   |        | test duration |        |
|           | Aldacide)  |          |        |               |        |
|           |            |          |        | \- - static   |        |
|           |            |          |        | test system   |        |
+-----------+------------+----------+--------+---------------+--------+

[Formaldehyde]{.underline}:

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]{.underline}:

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

[CONCLUSIONS]{.underline}:

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**

+-----------+-------------+----------+------+---------------+--------+
| **        | **          | **En     | **   | **Satisfies   | *      |
| Species** | Chemical,** | dpoint** | Toxi | Guidelines/** | *Refer |
|           |             |          | city |               | ence** |
|           | **% a.i.    | *        | Ca   | **Comments**  |        |
|           | Tested**    | *(ppm)** | tego |               | **(M   |
|           |             |          | ry** |               | RID)** |
+===========+=============+==========+======+===============+========+
| Waterflea | F           | LC~50~ = | Slig | **No          | 00     |
|           | ormaldehyde | 14.31    | htly | /supplemental | 148772 |
| (Daphnia  | 37%         |          | t    | study**       |        |
| magna)    |             |          | oxic |               |        |
|           | (as         |          |      | \- 48-hr test |        |
|           | S           |          |      | duration      |        |
|           | urflo-B315) |          |      |               |        |
|           |             |          |      | \- static     |        |
|           |             |          |      | test system   |        |
+-----------+-------------+----------+------+---------------+--------+

[Formaldehyde]{.underline}:

The results of a supplemental LC~50~ 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 EC~50~.

[Paraformaldehyde]{.underline}:

No data are available.

[CONCLUSIONS]{.underline}:

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** | **          | **Endp | **To   | **Satisfies   | *      |
|             | Chemical,** | oint** | xicity | Guidelines/** | *Refer |
|             |             |        | Cate   |               | ence** |
|             | **% a.i.    | **(    | gory** | **Comments**  |        |
|             | Tested**    | ppm)** |        |               | **(M   |
|             |             |        |        |               | RID)** |
+=============+=============+========+========+===============+========+
| Silverside  | F           | LC~50~ | Sl     | **Yes/core    | 00     |
|             | ormaldehyde | = 69   | ightly | study**       | 148770 |
| (Menidia    | 37%         |        | toxic  |               |        |
| enidia)     |             |        |        | \- 96-hr test |        |
|             |             |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Pink shrimp | F           | LC~50~ | Pract  | **Yes/core    | 00     |
| (Penaeus    | ormaldehyde | = 143  | ically | study**       | 148770 |
| duoratum)   | 37%         |        | no     |               |        |
|             |             |        | ntoxic | \- 96-hr test |        |
|             |             |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Pink shrimp | F           | LC~50~ | Mode   | **No          | 00     |
| (Penaeus    | ormaldehyde | = 7.6  | rately | /supplemental | 126396 |
| duorarum)   |             |        |        | study**       |        |
|             | 27.75%      |        | toxic  |               |        |
|             |             |        |        | \- 96-hr test |        |
|             | (as         |        |        | duration      |        |
|             | Surflo-B19) |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Pink shrimp | F           | LC~50~ | Pract  | **No          | 00     |
| (Penaeus    | ormaldehyde | = 358  | ically | /supplemental | 128086 |
| duorarum)   |             |        |        | study**       |        |
|             | 25.9%       |        | no     |               |        |
|             |             |        | ntoxic | \- 96-hr test |        |
|             | (as         |        |        | duration      |        |
|             | Surflo-B16) |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Pink shrimp | F           | LC~50~ | Sl     | **No          | 00     |
| (Penaeus    | ormaldehyde | = 12   | ightly | /supplemental | 126394 |
| duoratum)   |             |        |        | study**       |        |
|             | 32.37%      |        | toxic  |               |        |
|             |             |        |        | \- 96-hr test |        |
|             | (as         |        |        | duration      |        |
|             | Surflo-B17) |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Eastern     | F           | EC~50~ | Mode   | **Yes/core    | 00     |
| oyster      | ormaldehyde | = 1.8  | rately | study**       | 148770 |
| (           |             |        | toxic  |               |        |
| Crassostrea | 37%         |        |        | \- 48-hr test |        |
| virginica)  |             |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Eastern     | F           | EC~50~ | Highly | **No          | 00     |
| oyster      | ormaldehyde | = 0.30 | toxic  | /supplemental | 126396 |
| (           | 27.75%      |        |        | study**       |        |
| Crassostrea |             |        |        |               |        |
| virginica)  | (as         |        |        | \- 48-hr test |        |
|             | Surflo-B19) |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Eastern     | Formal      | EC~50~ | Mode   | **No          | 00     |
| oyster      | dehyde25.9% | = 2.9  | rately | /supplemental | 128086 |
| (           |             |        |        | study**       |        |
| Crassostrea | (as         |        | toxic  |               |        |
| virginica)  | Surflo-B16) |        |        | \- 48-hr test |        |
|             |             |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Eastern     | Formald     | EC~50~ | Highly | **No          | 00     |
| oyster      | ehyde32.37% | = 0.47 | toxic  | /supplemental | 126394 |
| (           |             |        |        | study**       |        |
| Crassostrea | (as         |        |        |               |        |
| virginica)  | Surflo-B17) |        |        | \- 48-hr test |        |
|             |             |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Fiddler     | F           | LC~50~ | Pract  | **No          | 00     |
| crab        | ormaldehyde | \>     | ically | /supplemental | 128086 |
|             | 25.9%       | 1000   | no     | study**       |        |
| (Uca        |             |        | ntoxic |               |        |
| pugilator)  | (as         |        |        | \- 96-hr test |        |
|             | Surflo-B16) |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Fiddler     | F           | EC~50~ | Pract  | **No          | 00     |
| crab        | ormaldehyde | = 380  | ically | /supplemental | 126396 |
|             |             |        | no     | study**       |        |
| (Uca        | 27.75%      |        | ntoxic |               |        |
| pugilator)  |             |        |        | \- 96-hr test |        |
|             | (as         |        |        | duration      |        |
|             | Surflo-B19) |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Fiddler     | F           | E      | Pract  | **No          | 00     |
| crab        | ormaldehyde | C~50~= | ically | /Supplemental | 126394 |
|             |             | 290    | no     | study**       |        |
| (Uca        | 32.37%      |        | ntoxic |               |        |
| pugilator)  |             |        |        | \- 96-hr test |        |
|             | (as         |        |        | duration      |        |
|             | S           |        |        |               |        |
|             | urflo-B-17) |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+
| Florida     | F           | LC~50~ | Sl     | **No          | 00     |
| pompano     | ormaldehyde | = 69   | ightly | /supplemental | 065640 |
|             |             |        | toxic  | study**       |        |
| (           | 37%         |        |        |               |        |
| Trachinotus |             |        |        | \- 96-hr test |        |
| carolinus)  |             |        |        | duration      |        |
|             |             |        |        |               |        |
|             |             |        |        | \- static     |        |
|             |             |        |        | test system   |        |
+-------------+-------------+--------+--------+---------------+--------+

# 

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

+-----------+---------------+--------+--------+---------------+--------+
| **        | **Chemical,** | **Endp | **To   | **Satisfies   | *      |
| Species** |               | oint** | xicity | Guidelines/** | *Refer |
|           | **% a.i.      |        | Cate   |               | ence** |
|           | Tested**      | **(    | gory** | **Comments**  |        |
|           |               | ppm)** |        |               | **(M   |
|           |               |        |        |               | RID)** |
+===========+===============+========+========+===============+========+
| Pink      | Par           | LC~50~ | Sl     | **Yes/core    | 00     |
| shrimp    | aformaldehyde | = 31   | ightly | study**       | 126395 |
| (Penaeus  |               |        | toxic  |               |        |
| duoratum) | 91%           |        |        | \- 96-hr test |        |
|           |               |        |        | duration      |        |
|           | (as Aldacide) |        |        |               |        |
|           |               |        |        | \- static     |        |
|           |               |        |        | test system   |        |
+-----------+---------------+--------+--------+---------------+--------+
| Eastern   | Par           | EC~50~ | Mode   | **Yes/core    | 00     |
| oyster    | aformaldehyde | \>3.2, | rately | study**       | 126395 |
| (Cr       |               | \<5.6  | toxic  |               |        |
| assostrea | 91%           |        |        | \- 48-hr test |        |
| v         |               |        |        | duration      |        |
| irginica) | (as Aldacide) |        |        |               |        |
|           |               |        |        | \- static     |        |
|           |               |        |        | test system   |        |
+-----------+---------------+--------+--------+---------------+--------+
| Fiddler   | Para          | LC~50~ | Pract  | **No          | 00     |
| crab      | formalde-hyde | = 213  | ically | /supplemental | 126395 |
|           |               |        | no     | study**       |        |
| (Uca      | 91%           |        | ntoxic |               |        |
| p         |               |        |        | \- 96-hr test |        |
| ugilator) | (as Aldacide) |        |        | duration      |        |
|           |               |        |        |               |        |
|           |               |        |        | \- static     |        |
|           |               |        |        | test system   |        |
+-----------+---------------+--------+--------+---------------+--------+

[Formaldehyde]{.underline}:

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]{.underline}:

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]{.underline}:

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.

[]{#__RefHeading___Toc195349028 .anchor}**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.

[]{#__RefHeading___Toc195349029 .anchor}**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."

[]{#__RefHeading___Toc195349030 .anchor}**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.

[]{#__RefHeading___Toc195349031 .anchor}**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]{.underline} 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.

[]{#__RefHeading___Toc195349032 .anchor}**11.0 REFERENCES**

**Product Chemistry References**

**MRID Citation**

**00146665** Celanese Chemical Co., Inc. (1985) \[Product Chemistry:
Formaldehyde 45%\]. Unpublished compilation. 19 p.

**41926001** Sibinovic, K. (1991) Reichold Formaldehyde/ Methanol:
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**42596708** Stupp, S. (1992) Product Chemistries and 30-Day Storage
Stability of Methaform 55A: (Product renamed Formaldehyde Solution 54):
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**42724601** Stupp, S. (1992) Product Chemistries and 30-Day Storage
Stability of Methaform 55A: (Product renamed Formaldehyde Solution 54):
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**42859001** Stupp, S. (1991) Product Chemistry and 30-Day Storage
Stability of Bactron K-55W Microbiocide: Lab Project Number:
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**42995401** Stupp, S. (1993) Product Chemistries and 30 Day Storage
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Unpublished study prepared by A&S Environmental Testing, Inc. 172 p.

**42930901** Stupp, S. (1992) Product Chemistries and 30 Day Storage
Stability of Formaldehyde Solution 54: Lab Project Number: CHAMP-01A-92.
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**43051601** Douglas, C. (1993) Formaldehyde-Product Identity Analysis
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**43745001** Sibinovic, K.; Tenhaeff, S. (1995) Product
Chemistry\--Formaldehyde Solution 37: Lab Project Number:
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**44952301** Sibinovic, K. (1999) Product Chemistry\--Formaldehyde
Solution 37F: Lab Project Number: CTI-99-PC-01. Unpublished study
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**Mammalian Toxicity References**

**MRID CITATION**

**00058054** Celanese Chemical Company (1976?) Toxicological Data and
Health Hazards: Formaldehyde. (Unpublished study received Nov 4, 1977
under 11558-8; CDL: 232282-K)

**00065508** Cannon Laboratories, Incorporated (1975) Summary of
Preservative DF-35 \# 3T1522: Laboratory Nos. 5E-6921, 5E-6923, 5E-6924,
5E- 6922. (Unpublished study received Jan 11, 1977 under 10000-4;
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**00065514** St. Pierre, F.; Parke, G.S.E. (1976) Report on Primary
Dermal Irritation Study in Rabbits: Laboratory No. 6E-4231. (Unpublished
study received Jan 11, 1977 under 10000-4; prepared by Cannon
Laboratories, Inc., submitted by Hallemite Lehn & Fink, Mont- vale,
N.J.; CDL:229296-G)

[]{.mark}

**00082134** Coon, R.A. et al. (1970) Animal Inhalation Studies on
Ammonia, Ethylene Glycol, Formaldehyde, Dimethylamine, and Ethanol.
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[]{.mark}

**00082136** Schnurer, L.B. (1963) Maternal and foetal responses to
chronic stress in pregnancy: A study in albino rats. Acta
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Richmond, Calif.; CDL:095383-A)

[]{.mark}

**00123769** Ranstrom, S. and Schrurer, L. (1956) Stress and Pregnancy.
Acta Pathol. Microbiol. Scandinavia. Supplement III, 113-114.

[]{.mark}

**00123770** Schnurer, L. (1963) Maternal and foetal responses to
chronic stress in pregnancy. Acta Endocrinologica (80):3-96. (Also In
unpublished submission received 1963 under 4G1438; submitted by Chevron
Chemical Co., Richmond, CA; CDL:093832-T)

[]{.mark}

**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
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**00132156** Jagannath, D. (1978) Mutagenicity Evaluation of Dantoin
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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)

**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).

**00132168** Thilagar, A.; Kumaroo, P.; Pant, K. (1982) Cytogenicity
Study: Chinese 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)

**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)

**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)

[]{.mark}

**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.

[]{.mark}

**00143289** Kerns, W.D. et al. (1983) Carcinogenicity of Formaldehyde
in Rats and Mice after Long-Term Inhalation Exposure. Cancer Research
43: 4382-4392.

[]{.mark}

**00143291** Hurni, H. and H. Odher (1972) Reproduction Study with
Formaldehyde and Hexamethylenetetr-amine in Beagle Dogs. Fd. Cosmet.
Toxicol. 11: 459-462.

[]{.mark}

**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.

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**APPENDIX A -- Physical and Chemical Properties of**

**Formaldehyde and Paraformaldehyde**

+---------------+----------------------------+-------------------------+
| **Table A1.   |                            |                         |
| Phys          |                            |                         |
| ical/Chemical |                            |                         |
| Properties    |                            |                         |
| for           |                            |                         |
| Formaldehyde  |                            |                         |
| and           |                            |                         |
| Paraf         |                            |                         |
| ormaldehyde** |                            |                         |
+===============+============================+=========================+
| **Parameter** | **Formaldehyde**           | **Paraformaldehyde**    |
+---------------+----------------------------+-------------------------+
| **Molecular   | 30.03 (Gas)                | (30.03)n g/mole         |
| Weight**      |                            |                         |
|               | 48.03 (Aqueous solution)   |                         |
+---------------+----------------------------+-------------------------+
| **Color**     | Clear Colorless (54%       | White prill             |
|               | soln.)                     |                         |
|               |                            | White crystalline solid |
|               | Clear Colorless (37%       |                         |
|               | soln.)                     | White solid flakes      |
|               |                            |                         |
|               | Colorless (Gas)            |                         |
+---------------+----------------------------+-------------------------+
| **Physical    | Liquid (54% solution)      | Solid, flakes, Powder   |
| State**       |                            |                         |
|               | Liquid (37% solution)      |                         |
|               |                            |                         |
|               | Gas                        |                         |
+---------------+----------------------------+-------------------------+
| **Odor**      | Pungent (54% solution)     | Pungent formaldehyde    |
|               |                            | odor                    |
|               | Pungent (37% solution)     |                         |
|               |                            |                         |
|               | Pungent, suffocating       |                         |
|               | irritating odor (Gas)      |                         |
+---------------+----------------------------+-------------------------+
| **Melting     | N/A (54% & 37% solution)   | 120 to 170ºC closed     |
| Point**       |                            | tube                    |
|               | N/A (Gas at room           |                         |
|               | temperature)               |                         |
|               |                            |                         |
|               | -92ºC (Gas)                |                         |
+---------------+----------------------------+-------------------------+
| **Boiling     | \~100ºC (54% solution)     | Solid at ambient        |
| Point**       |                            | temperature             |
|               | 101ºC (214ºF) (37% soln.)  |                         |
|               |                            | Slowly sublimes to      |
|               | -19.5ºC (-3ºF) -- (Gas)    | formaldehyde gas.       |
|               |                            |                         |
|               | -21ºC (Gas)                | 760 mm Hg               |
|               |                            |                         |
|               |                            | Sublimes at 150ºC       |
+---------------+----------------------------+-------------------------+
| *             | 8.83 lbs/gal -- 54% soln   | 750 to 850 kg/m3        |
| *Density/Bulk |                            |                         |
| Den           | Sp gr. 1.067 -- 54% soln   | Density: 1.46 g/ml @    |
| sity/Specific |                            | 15ºC                    |
| Gravity**     | 8.75 to 9 lbs/gal -- 37%   |                         |
|               | soln                       | Density varies with     |
|               |                            | particle size and       |
|               | Sp gr. 1.05 at 75ºF -- 37% | degree of compaction.   |
|               | soln                       |                         |
|               |                            | Free flowing: approx.   |
|               | Sp gr. 1.08 at 20ºC -- 37% | 37 lbs/cu ft            |
|               | soln                       |                         |
|               |                            | Packed: approx. 42      |
|               | 0.8153 gm/cm^3^ @ 20ºC     | lbs/cu ft               |
|               | (Gas)                      |                         |
|               |                            | Sp Gr. 1.40             |
|               | 0.815 g/mL at 20ºC (Gas)   |                         |
|               |                            |                         |
|               | 1•kg·m^-3^ (Gas)           |                         |
+---------------+----------------------------+-------------------------+
| **Solubility  | At low temperatures,       | Acetone: Soluble to     |
| in organic    | liquid formaldehyde is     | insoluble               |
| solvents at   | miscible in all            |                         |
| 25˚C (g/100   | proportions with a wide    | Dilute Alkali: Very     |
| ml)**         | variety of non-polar       | Soluble                 |
|               | organic solvents such as   |                         |
|               | toluene, ether, chloroform | Dilute Acid: Very       |
|               | and ethyl acetate.         | Soluble                 |
|               |                            |                         |
|               | Polar solvents such as     | Insoluble in alcohol,   |
|               | alcohols, amines or acids  | ether. Insoluble in     |
|               | either act as              | most organic solvents.  |
|               | polymerization catalysts   | (TOXNET).               |
|               | or react to form methylol  |                         |
|               | or methylene derivatives.  | **Solubility (Room      |
|               |                            | Temperature):**         |
|               | Soluble in ether, alcohol, |                         |
|               | acetone, and benzene.      | • Ethanol 2.37%         |
|               |                            |                         |
|               |                            | • Methanol 4.71%        |
|               |                            |                         |
|               |                            | • Hexane 5.10 ppm       |
|               |                            |                         |
|               |                            | • Ether 108 ppm         |
|               |                            |                         |
|               |                            | • 1.0 N NaOH 22.9%      |
|               |                            |                         |
|               |                            | • 0.1N NaOH 22.8%       |
+---------------+----------------------------+-------------------------+
| *             | Miscibility 100% in water  | \>90% in water at pH    |
| *Solubility** | (54% & 37% solutions).     | 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       | 40 mmHg 30ºC -- 54% soln   | 1.45 pCH~2~ (mm)        |
| Pressure**    |                            | depolymerization        |
|               | 40 mmHg 30ºC -- 37% soln   | pressure at 25ºC        |
| **Vapor       |                            |                         |
| Density**     | 1 mm Hg **/**Formalin      | 1 mm Hg @ 30ºC          |
|               | (TOXNET)                   |                         |
|               |                            | 1.4 mm Hg \@25ºC        |
|               | A 37% formaldehyde         |                         |
|               | solution has a vapor       | 1.55 mm Hg              |
|               | pressure of about 1.3 mm   |                         |
|               | Hg at 68ºF, and 67 - 88 mm | \@30ºC mm Hg Dry Air 1; |
|               | Hg at 98ºF                 | Dew point 3             |
|               |                            |                         |
|               | 3,890 mm Hg @ 25ºC (Gas)   | \@60ºC mm Hg Dry Air 5; |
|               | (TOXNET)                   | Dew point 15            |
|               |                            |                         |
|               | 1.04 (Air=1 at 20 deg. C)  | 10.5 mm Hg @ 25ºC       |
|               | (Gas)                      | (TOXNET)                |
|               |                            |                         |
|               |                            | 1.03 (Air=1)            |
+---------------+----------------------------+-------------------------+
| *             | (54%)The dissociation      | 1.6 x 10E-13 aqueous    |
| *Dissociation | constant in a water        | formaldehyde no formic  |
| constants in  | solution at 25ºC is 1.62 x | acid                    |
| water**       | 10^-13^                    |                         |
|               |                            | 1.8 x l0E-4 for formic  |
|               | [37% soln.]{.underline}:   | acid                    |
|               |                            |                         |
|               | 1.6 X 1OE^-13^ aqueous     | pKa = 15.50 @ 25ºC      |
|               | formaldehyde, no formic    | (TOXNET)                |
|               | acid.                      |                         |
|               |                            |                         |
|               | 1.8 X 1OE^-4^ for formic   |                         |
|               | acid.                      |                         |
|               |                            |                         |
|               | Formaldehyde will have no  |                         |
|               | dissociation constant In   |                         |
|               | the gaseous state.         |                         |
+---------------+----------------------------+-------------------------+
| **Partition   | 1.06 at a concentration of | -0.65 (calculated)      |
| coefficient** | 25.42% (Gas)               |                         |
|               |                            |                         |
| **(n-octanol  | -0.65 (calculated)         |                         |
| / water)**    |                            |                         |
|               | log Kow= 0.35 (Gas)        |                         |
|               | (TOXNET/ EPI Suite)        |                         |
+---------------+----------------------------+-------------------------+
| **pH**        | 5.5 -- 6.2 (54% soln)      | 3.5 -- 4.5 (In aqueous  |
|               |                            | solution)               |
|               | 5.83 (54% soln)            |                         |
|               |                            | A 5% suspension in      |
|               | 3.5 -- 4.5 (37% soln)      | water is neutral to     |
|               |                            | litmus (TOXNET).        |
|               | 4 to 5 (37% soln)          |                         |
|               |                            |                         |
|               | Formaldehyde gas has no pH |                         |
+---------------+----------------------------+-------------------------+
| **Stability   | \>30 days at 50ºC (54%     | Stable.                 |
| to normal and | soln)                      |                         |
| elevated      |                            | Paraformaldehyde is     |
| te            | A thirty-seven percent     | stable on exposure to   |
| mperatures.** | (37%) formaldehyde/water   | sunlight, elevated      |
|               | solution is stable at 35ºC | temperatures (54°C) and |
| **Stability   | for periods of six months  | elemental metals,       |
| to metals.**  | to one year.               | copper, iron and        |
|               |                            | aluminum.               |
| **Stability   | In excess of 2 years (37%  |                         |
| to metal      | soln)                      | Stable under ordinary   |
| ions.**       |                            | conditions of use and   |
|               | Stable under ordinary      | storage. Releases       |
|               | conditions of use and      | formaldehyde gas slowly |
|               | storage (37%).             | as it sublimes at room  |
|               |                            | temperatures. (Slowly   |
|               | Formaldehyde gas is        | sublimes to             |
|               | unstable and can           | formaldehyde).          |
|               | polymerize quite easily    |                         |
|               | (Gas).                     | High temperature causes |
|               |                            | liberation of           |
|               |                            | formaldehyde gas.       |
|               |                            |                         |
|               |                            | Stable for up to 12     |
|               |                            | months when stored at   |
|               |                            | ambient temperatures.   |
+---------------+----------------------------+-------------------------+
| **F           | Closed cup (PM) +54ºF (54% | \~71ºC tag closed cup;  |
| lammability** | soln)                      | 93ºC                    |
|               |                            |                         |
|               | \~100ºF (54%)              | Flash point: 70°C       |
|               |                            |                         |
|               | Flash Pt. 134ºF            | 158F Tag Closed Cup     |
|               |                            | (TCC)                   |
|               | Flash point: 122ºF (37%    |                         |
|               | soln)                      | 200F Tag Open Cup (TOC) |
|               |                            |                         |
|               | \>140ºF -- 37% soln        | **Flash Points:**       |
|               |                            | Closed Cup: 70°C        |
|               | Flashpoint 60ºC (Gas)      | (158°F).                |
|               |                            |                         |
|               | Flammability limits at     | 158F Tag Closed Cup     |
|               | 25ºC 7--73%                | (TCC)                   |
|               |                            |                         |
|               | Autoignition temperature   | 200F Tag Open Cup (TOC) |
|               | 300ºC                      |                         |
|               |                            |                         |
|               | Flammable (Gas)            |                         |
+---------------+----------------------------+-------------------------+
| **Storage     | \>30 days at 50ºC (54% &   | Stable for up to 12     |
| stability**   | 37% solutions)             | months when stored at   |
|               |                            | ambient temperatures.   |
|               | A thirty-seven percent     |                         |
|               | formaldehyde/water         | Product must be store   |
|               | solution is stable at 35ºC | at temperatures not     |
|               | for periods of six months  | higher than 25ºC.       |
|               | to one year.               |                         |
|               |                            |                         |
|               | Formaldehyde gas is        |                         |
|               | unstable and can           |                         |
|               | polymerize quite easily.   |                         |
+---------------+----------------------------+-------------------------+
| **Ex          | Upper \~70%; Lower \~7%    | Upper\~70%; Lower\~7%   |
| plodability** | (54% & 37% soln)           |                         |
|               |                            | Explosion limits: 7.0   |
|               | [37% Soln]{.underline}:    | -- 73%                  |
|               |                            |                         |
|               | Lower Explosion Limit: 7   | Autoignition temp:      |
|               | %\                         | 300ºC (572ºF)           |
|               | Upper Explosion Limit: 73% |                         |
+---------------+----------------------------+-------------------------+
| **Viscosity** | 3 -- 5 CPS @ 25ºC (54%     | N/A Product is solid at |
|               | soln.)                     | 25ºC                    |
|               |                            |                         |
|               | 5--10 CPS @ 75ºC (37%      |                         |
|               | soln)                      |                         |
+---------------+----------------------------+-------------------------+
| **            | Miscibility 100% in water  | \~90% in water at pH    |
| Miscibility** | (54% & 37% solutions)      | 9.0                     |
+---------------+----------------------------+-------------------------+
| **Corrosion   | Moderate (54% & 37%        | Moderate                |
| Cha           | solns.)                    |                         |
| racteristic** |                            |                         |
|               | Aqueous formaldehyde is    |                         |
|               | corrosive to carbon steel  |                         |
|               | (TOXNET)                   |                         |
|               |                            |                         |
|               | Corrosive to metal (Gas)   |                         |
+---------------+----------------------------+-------------------------+
| **Dielectric  | 45e \@20ºC                 | \~450e \@20ºC           |
| Breakdown     |                            |                         |
| Voltage**     | N/A                        |                         |
+---------------+----------------------------+-------------------------+
| **Oxidati     | Oxidation:                 | **Oxidation:**          |
| on/Reduction: |                            |                         |
| Chemical      | 2HCHO + H~2~O~2~ + 2NaOH   | 2HCHO + H202 + 2NaOH \> |
| Inco          | \> 2HCOONa + 2H~2~O + H~2~ | 2HCOONa + 2H20 + H2     |
| mpatibility** |                            |                         |
|               | HCHO + ½ O~2~ \> HCOOH     | HCH0+1/2 O2 \> HCOOH    |
|               |                            |                         |
|               | HCHO + O~2~ \> CO~2~ +     | HCHO + 02 \> C02 + H20  |
|               | H~2~O \[Requires very high | \[Requires very high    |
|               | temperatures \> 300 ºC\]   | temp - \>300°C\]        |
|               |                            |                         |
|               | 2HCHO + O~2~ \> 2CO +      | 2HCHO +02 \> 2C0 + 2H20 |
|               | 2H~2~O                     |                         |
|               |                            | **Reduction:**          |
|               | Reduction:                 |                         |
|               |                            | HCHO + H2 \< \> CH3OH   |
|               | HCHO + H~2~ \< \> CH~3~OH  |                         |
|               |                            | **Incompatibility:**    |
|               | [37% soln]{.underline}:    |                         |
|               | Reacts with alkalies,      | Incompatible with       |
|               | acids, and oxidizers.      | strong acids, organic   |
|               |                            | acids, strong oxidizing |
|               | .                          |                         |
|               |                            | agents, oxides,         |
|               | **Incompatibility          | alkalies, strong bases, |
|               | (Materials to Avoid)**:    | amines. Combustible.    |
|               | Strong oxidizing agents,   | Dust may form an        |
|               | caustics, strong alkalies, | explosive mixture with  |
|               | isocyanates, anhydrides,   | air. Liberates          |
|               | oxides, and inorganic      | poisonous gases on      |
|               | acids.                     | combustion.             |
|               |                            |                         |
|               | [Gas]{.underline}:         | **Incompatibilities:**  |
|               | **Incompatibilities:**     |                         |
|               | Reacts explosively with    | Caustics, strong        |
|               | peroxides, nitrogen oxide  | alkalis, isocyanates,   |
|               | and performic acid; can    | anhydrides, oxides and  |
|               | react with hydrogen        | inorganic acids.        |
|               | chloride or other          |                         |
|               | inorganic chlorides to     | Paraformaldehyde or     |
|               | form                       | concentrated formalin   |
|               | bis(chloromethyl)ether     | solutions may react     |
|               | (Source: Literature)       | 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          |                           |                          |
| Parafo       |                           |                          |
| rmaldehyde** |                           |                          |
+==============+===========================+==========================+
| **Guideline  | **MRID Number (Year)/**   | **Results**              |
| Number/**    |                           |                          |
|              | **Citation/**             |                          |
| **Study      | **Classification/ Doses** |                          |
| Type/**      |                           |                          |
|              |                           |                          |
| **Test       |                           |                          |
| Substance (% |                           |                          |
| a.i.)**      |                           |                          |
+--------------+---------------------------+--------------------------+
| **Subchronic |                           |                          |
| Toxicity**   |                           |                          |
+--------------+---------------------------+--------------------------+
| 870.3100     | **MRID 00124677**         | **NOAEL: 0.3%**          |
|              |                           | formaldehyde             |
| 90-Day oral  | Driedger, A.; Walker, J.; |                          |
| toxicity in  | Galloway, F. (1973)       | **LOAEL: 0.6%**          |
| rodents      | Letter sent to C. Smart   | formaldehyde, based on   |
|              | dated Oct 1, 1973: "Rat   | irritability, weight     |
| Purity: 37%  | tolerance to Dietary      | loss, hair loss,         |
| a.i.         | Formaldehyde: Reference   | yellowing of teeth, and  |
|              | No. AD-114-73,            | decreased food           |
|              | JRW-341-73." (Unpublished | consumption              |
|              | study; submitted by       |                          |
|              | Celanese Chemical Co.,    | Rats exposed to          |
|              | Dallas, TX; CDL:094622-H) | concentrations of 0.6%   |
|              |                           | formaldehyde and higher  |
|              | **Not Reviewed**          | exhibited dose-related   |
|              |                           | increases in             |
|              | 10 male Holtzman          | irritability,            |
|              | rats/dose                 | disability, hair loss,   |
|              |                           | and yellowing of teeth   |
|              | 0, 0.3, 0.6, 1.2, or 2.4  | and dose-related         |
|              | % formaldehyde            | decreased food           |
|              |                           | consumption. Growth      |
|              |                           | rates significantly      |
|              |                           | different from controls  |
|              |                           | are expected at          |
|              |                           | formaldehyde             |
|              |                           | concentrations ≥ 0.50 %, |
|              |                           | believed due to          |
|              |                           | decreased food           |
|              |                           | consumption.             |
+--------------+---------------------------+--------------------------+
| 870.3100     | **MRID 00134114**         | Statistical evaluation   |
|              |                           | of overall body weight   |
| 28-Day oral  | Viguera, C.; Kundzins, M. | gains and total food     |
| toxicity in  | (1960) "28-Day Oral       | consumption revealed no  |
| rodents      | Administration\--Rats:    | significant differences  |
|              | U.F. Concentrate-85\|."   | between the control      |
| Purity: 60%  | (Unpublished study;       | group and test groups.   |
| a.i.         | prepared by Hazleton      | The appearance and       |
|              | Laboratories, Inc.; CDL:  | behavior of the test     |
|              | 105284-C)                 | rats were comparable to  |
|              |                           | those of the control     |
|              | **Not Reviewed**          | rats. No pathological    |
|              |                           | findings associated with |
|              | 10 Male Sprague-Dawley    | the oral administration  |
|              | rats/dose                 | of the test substance    |
|              |                           | were observed.           |
|              | 0, 79, 158, or 316        |                          |
|              | uL/kg/day, once daily, 5  | One rat exposed to 158   |
|              | days/ week, 20 doses      | 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     | Johannsen, F.R., G.J.     | **NOAEL: 50 mg/kg/day    |
|              | Levinskas A.S. Tegris     | (M), 100 mg/kg/day (F)** |
| 90-Day oral  | (1986) Effects of         |                          |
| toxicity in  | Formaldehyde in the Rat   | **LOAEL: 100 mg/kg/day   |
| rodents      | and Dog following Oral    | (M), 150 mg/kg/day       |
|              | Exposure. Toxicology      | (F)**, based on          |
| Purity: 95%  | Letters 30: 1-6.          | decreased body weight    |
| a.i.,        |                           | gain                     |
| aqueous      | **Open Literature**       |                          |
| para         |                           | No deaths or abnormal    |
| formaldehyde | Sprague-Dawley Albino Rat | reactions were observed  |
|              |                           | in rats administered     |
|              | (15/sex/dose)             | formaldehyde for 90      |
|              |                           | days. Significant        |
|              | Formaldehyde was          | reductions in weight     |
|              | administered in the       | gain were observed in    |
|              | drinking-water at target  | both sexes at 150 mg/kg  |
|              | doses of 0, 50, 100, or   | and in male rats given   |
|              | 150 mg/kg bw/d for 13     | 100 mg/kg. There was a   |
|              | weeks (91 consecutive     | dose-related decrease in |
|              | days)                     | 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                       |
|              |                           | s                        |
|              |                           | tatistically-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     | Til, H.P., et al. (1988)  | **NOAEL= 25 mg/kg/day**  |
|              | Evaluation of the Oral    |                          |
| 28-Day oral  | Toxicity of Acetaldehyde  | **LOAEL = 125            |
| toxicity in  | and Formaldehyde in a     | mg/kg/day**, based on    |
| rodents      | 4-week Drinking Water     | yellowish fur from week  |
|              | Study in Rats. Fd. Chem.  | 3 onward, decreased food |
| Para         | Toxic. 26(5): 447-452.    | intake, decreased        |
| formaldehyde |                           | protein and albumin      |
| (95% a.i.,   | **Open Literature**       | levels in blood plasma,  |
| aqueous)     |                           | and histologic changes.  |
|              | Rat (10/sex/dose)         |                          |
|              |                           | There were no deaths and |
|              | 0, 5, 25, or 125          | the rats appeared        |
|              | mg/kg/day; a              | healthy throughout the   |
|              | water-restricted group    | study.                   |
|              | (10/sex) received the     |                          |
|              | same amount of water as   | The fur of the rats      |
|              | liquid consumed by the    | receiving 125 mg/kg/day  |
|              | high-dose groups          | 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     | Johannsen, F.R., G.J.     | **NOAEL: 75 mg/kg/day    |
|              | Levinskas, A.S. Tegris.   | (M/F)**                  |
| 90-Day oral  | (1986). Effects of        |                          |
| toxicity in  | Formaldehyde in the Rat   | **LOAEL: 100 mg/kg/day   |
| nonrodents   | and Dog following Oral    | (M/F)**, based on        |
|              | Exposure. Toxicology      | reduced weight gain      |
| Purity:      | Letters 30: 1-6.          |                          |
| Para         |                           | No deaths or abnormal    |
| formaldehyde | **Open Literature**       | reactions were observed. |
| (95% a.i.,   |                           | Significant reductions   |
| aqueous)     | Beagle Dog (4/sex/dose)   | in weight gain were      |
|              |                           | observed in both sexes   |
|              | 0, 50, 75, or 100         | at 100 mg/kg/day.        |
|              | mg/kg/day in drinking     | Treated animals had      |
|              | water for 90 days         | 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     | **MRID 00082134**         | One of the 15 rats died; |
|              |                           | none of the other        |
| 90-Day       | Coon, R.A. et al. (1970)  | animals showed signs of  |
| inhalation   | Animal Inhalation Studies | illness or toxicity.     |
| toxicity     | on Ammonia, Ethylene      | Hematologic values were  |
|              | Glycol, Formaldehyde,     | normal. On               |
|              | Dimethylamine, and        | histopathologic          |
|              | Ethanol. Toxicology and   | examination, the lungs   |
|              | Applied Pharmacology 16:  | of all species           |
|              | 646-655.                  | consistently showed      |
|              |                           | varying degrees of       |
|              | **Not Reviewed**          | interstitial             |
|              |                           | inflammation. The hearts |
|              | 15 Sprague-Dawley and     | and kidneys from guinea  |
|              | Long-Evans rats (M/F), 15 | pigs and rats showed     |
|              | Princeton-derived guinea  | focal chronic            |
|              | pigs (M/F), 3 New Zealand | inflammatory changes.    |
|              | rabbits (M), 3 squirrel   |                          |
|              | monkeys (M), 2 Beagle     |                          |
|              | dogs (M)                  |                          |
|              |                           |                          |
|              | Formaldehyde Continuous   |                          |
|              | exposure to 4.6 mg/m^3^,  |                          |
|              | 8 hours/day, 5 days/week, |                          |
|              | 6 weeks                   |                          |
+--------------+---------------------------+--------------------------+
| 870.3465     | **MRID 00149755**         | Treatment-related        |
|              |                           | effects during the study |
| 6-Week       | Rusch, G.; Rinehart, W.   | were not seen. Compared  |
| inhalation   | (1980) A 26 Week          | to controls, monkeys     |
| toxicity     | Inhalation Toxicity Study | receiving 1.00 ppm       |
|              | of Formaldehyde in        | showed increased         |
| Purity =     | Monkey, Rat, and Hamster: | incidence of dried       |
| 4.96%        | Project No. 79- 7259.     | material around the      |
|              | Unpublished study         | nose, increased          |
|              | prepared by Bio/dynamics  | incidences of hoarseness |
|              | Inc. 184 p.               | and congestion.          |
|              |                           |                          |
|              | **Core-Supplementary**    | [Body                    |
|              |                           | weight]{.underline}      |
|              | Fisher 344 rats --        |                          |
|              | 10/sex/dose; Syrian       | Compared to controls, no |
|              | golden hamsters --        | significant body weight  |
|              | 10/sex/doseand            | changes were seen for    |
|              | Cynomolgous monkeys -- 6  | monkeys and hamsters     |
|              | males/dose                | throughout the study.    |
|              |                           | The 3 ppm male and       |
|              | []{.mark}                 | female rats showed       |
|              |                           | significant differences  |
|              | Test material             | (p ≤ 0.01) from week     |
|              | (Formaldehyde, Lot        | 2-26 compared to         |
|              | #0611N-79) was            | controls.                |
|              | administered at 0, 0,     |                          |
|              | 0.20, 1.00, or 3.00 ppm   | [Organ                   |
|              | equivalent to 0, 0, 0.19, | weight]{.underline}      |
|              | 0.98 and 2.95 ppm,        |                          |
|              | respectively, for 26      | Organ weights for        |
|              | weeks.                    | monkeys and hamsters     |
|              |                           | were not significantly   |
|              | []{.mark}                 | 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]{.underline}   |
|              |                           |                          |
|              |                           | In monkeys, hamsters and |
|              |                           | rats, no abnormalities   |
|              |                           | were seen in or          |
|              |                           | attributable to          |
|              |                           | formaldehyde vapors.     |
+--------------+---------------------------+--------------------------+
| 870.3465     | Woutersen, R.A. et al.    | **NOAEL: 1.2 mg/m^3^**   |
|              | (1987) Subchronic         |                          |
| 90-Day       | (13-week) Inhalation      | **LOAEL: 12 mg/m^3^**    |
| inhalation   | Toxicity Study of         |                          |
| toxicity     | Formaldehyde in Rats.     | In the high-dose group,  |
|              | Journal of Applied        | uncoordinated            |
| Purity:      | Toxicology, 7(1): 43-49.  | locomotion, and climbing |
| 97-99% a.i.  |                           | of the cage walls were   |
|              | **Open Literature**       | observed only during the |
|              |                           | 1st 30 minutes of each   |
|              | Rats (10/sex/dose)        | exposure period.         |
|              |                           | S                        |
|              | 0, 1.0, 10, or 20 ppm (0, | tatistically-significant |
|              | 1.2, 12, or 24 mg/m^3^),  | growth retardation       |
|              | 6 hr/day, 5 days/week     | 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/m^3^ 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/m^3^ 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     | Appelman, L.M. et al.     | **NOAEL = 1.24 mg/m^3^** |
|              | (1988) One-year           |                          |
| 90-Day       | Inhalation Toxicity Study | **LOAEL = 12.4           |
| inhalation   | of Formaldehyde in Male   | mg/m^3^**, based on body |
| toxicity     | Rats with a Damaged or    | weight retardation,      |
|              | Undamaged Nasal Mucosa.   | incidence of oliguria,   |
|              | Journal of Applied        | and incidence of lesions |
|              | Toxicology, 8(2): 85-90.  | of the respiratory and   |
|              |                           | olfactory epitheliums    |
|              | **Open Literature**       | for damaged and          |
|              |                           | undamaged animals        |
|              | Male albino Wistar rats   |                          |
|              | (Cpb:WU) -40/dose         | The nose damaged by      |
|              |                           | electrocoagulation is    |
|              | Formaldehyde exposure via | more susceptible to      |
|              | inhalation route for 6    | cytotoxic action of      |
|              | hr/day, 5 days/week, 13   | formaldehyde than the    |
|              | or 52 weeks at            | undamaged nose.          |
|              | concentrations of 0.1, 1, |                          |
|              | or 10 ppm (0, 0.12, 1.24, | 8 animals (7 with        |
|              | or 12.4 mg/m^3^), 1/2     | damaged and 1 with       |
|              | with bilaterally damaged  | undamaged nose) randomly |
|              | nasal mucosa              | 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/m^3^ 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/m^3^   |
|              |                           | dose group. In the       |
|              |                           | damaged 12.4 mg/m^3^     |
|              |                           | dose group, focal        |
|              |                           | thinning/ disarrangement |
|              |                           | of the olfactory         |
|              |                           | epithelium was           |
|              |                           | identified (p\<0.05).    |
|              |                           |                          |
|              |                           | 52 weeks: The undamaged  |
|              |                           | 0.12 mg/m^3^ and 1.24    |
|              |                           | mg/m^3^ dose groups      |
|              |                           | displayed squamous       |
|              |                           | metaplasia of the        |
|              |                           | respiratory epithelium   |
|              |                           | (p\<0.05). At 12.4       |
|              |                           | mg/m^3^, the undamaged   |
|              |                           | group had squamous       |
|              |                           | metaplasia, basal cell   |
|              |                           | hyperplasia, and focal   |
|              |                           | rhinitis (p\<0.05) of    |
|              |                           | the respiratory          |
|              |                           | epithelium. The 12.4     |
|              |                           | mg/m^3^ 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     | Chemical Industry         | **NOAEL = 4 ppm (LDT)**  |
|              | Institute of Technology   |                          |
| 90-Day       | -- info in memo but study | **Systemic LOAEL = 12.7  |
| inhalation   | untraceable               | ppm,** based on body     |
| toxicity     |                           | weight decrease and      |
|              | 20 Mice and Rats          | nasal erosion.           |
| Purity = ??? |                           |                          |
|              | Test material             | No adverse effects       |
|              | administered at           | observed in the 4 ppm    |
|              | concentrations of 4,      | group. At 12.7 ppm, a    |
|              | 12.7, or 38.6 ppm for 6   | decrease in body weight  |
|              | hours each day, five days | and evidence of nasal    |
|              | a week for 13 weeks.      | erosion in two exposed   |
|              |                           | rats was observed.       |
|              | []{.mark}                 | Ulceration and necrosis  |
|              |                           | of the nasal mucosa seen |
|              |                           | at 38.6 ppm resulted in  |
|              |                           | termination of exposure  |
|              |                           | after 2 weeks.           |
+--------------+---------------------------+--------------------------+
| 870.3465     | -- citation not provided  | **Systemic NOAEL = 0.028 |
|              | in memo                   | ppm**                    |
| 90-Day       |                           |                          |
| inhalation   | Test material             | **Systemic LOAEL = 0.82  |
| toxicity     | administered at           | ppm,** base don          |
|              | concentrations of 0.0098, | proliferation of         |
| Purity = ??? | 0.028, 0.82, or 2.4 ppm   | lymphocytes, histiocytes |
|              | for 3 months.             | in the lungs,            |
|              |                           | perivascular hyperemia.  |
|              | 25 Rats                   |                          |
|              |                           | **ChE NOAEL = 0.82 ppm** |
|              | []{.mark}                 |                          |
|              |                           | **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     | Dubreuil, A., G. Bouley,  | **NOAEL = 1.6 ppm**      |
|              | J. Godin, and C. Boudène. |                          |
| 90-Day       | (1976). Continuous        | The only adverse effect  |
| inhalation   | inhalation of low-level   | seen at 1.6 ppm was      |
| toxicity     | doses of formaldehyde:    | discoloration of hair.   |
|              | Experimental study on the | The 4.55 ppm group was   |
| Purity: Not  | rat. Eur. J. Toxicol.     | exposed for 45 days and  |
| Reported     | 9:245-250.                | had a decrease in rate   |
|              |                           | of weight gain. The 8.07 |
|              | **Open Literature**       | ppm was exposed for 60   |
|              |                           | days and has respiratory |
|              | []{.mark}                 | and eye irritation, a    |
|              |                           | decrease in food         |
|              | 25 rats                   | consumption, and a       |
|              |                           | decease in liver weight. |
|              | []{.mark}                 |                          |
|              |                           |                          |
|              | Test material             |                          |
|              | administered at           |                          |
|              | concentrations of 1.6,    |                          |
|              | 4.55, or 8.07 ppm for     |                          |
|              | 45-90 days.               |                          |
+--------------+---------------------------+--------------------------+
| **D          |                           |                          |
| evelopmental |                           |                          |
| Toxicity**   |                           |                          |
+--------------+---------------------------+--------------------------+
| 870.3700a    | **MRID 00082136,          | Formalin exposure        |
|              | 00123770**                | resulted in small,       |
| Prenatal     |                           | subcutaneous necroses.   |
| D            | Schnurer, Lars- Bentil    | No differences in smear  |
| evelopmental | (1963) Maternal and Fetal | cytology were noted      |
| Toxicity     | Responses to Chronic      | between the pregnant     |
|              | Stress in Pregnancy: A    | treated and pregnant     |
| Purity: 35%  | Study in Albino Rats.     | control rats.            |
| a.i.         | Acta Endocrinologica,     |                          |
|              | Supplement 80: 1-96.      | No stress-induced        |
|              |                           | changes of the gastric   |
|              | **Not Reviewed**          | mucosa were seen. The    |
|              |                           | following treatment-     |
|              | Rats (56, 67, 50,         | related organ weight     |
|              | 44/group, respectively)   | changes were observed:   |
|              |                           | thyroid weight was       |
|              | Subcutaneous injection,   | significantly lower in   |
|              | Pregnant rats exposed to  | formaldehyde-exposed     |
|              | 0.25 mL of 2% solution,   | non-pregnant rats;       |
|              | pregnant control rats,    | adrenal weights          |
|              | non-pregnant rats exposed | increased significantly  |
|              | to 0.25 mL of 2%, control | in exposed non-pregnant  |
|              | non- pregnant rats;       | rats.                    |
|              | 2x/day, GD 2-19 to 22     |                          |
|              |                           | 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    | **MRID 00123769**         | The fetuses showed       |
|              |                           | higher mean weight (5.1  |
| Prenatal     | Ranstrom, S. and          | gm) in comparison with   |
|              | Schrurer, L. (1956)       | the controls (4.7 gm).   |
| D            | Stress and Pregnancy.     | The fetuses of the       |
| evelopmental | Acta Pathol. Microbiol.   | treated group showed     |
| Toxicity     | Scandinavia. Supplement   | further-lower adrenal    |
| (rodent);    | III, 113-114.             | weight, the difference   |
| Purity: 6%   |                           | was greater in the       |
|              | **Not Reviewed**          | fetuses with low body    |
|              |                           | weight than in those     |
|              | Pregnant rats were        | with a high one. They    |
|              | treated with subcutaneous | also seemed to show more |
|              | injections of formalin    | rapid disappearance of   |
|              | solution 0.25 ml during   | extramedullary           |
|              | gestation. Just before    | hematopoiesis than the   |
|              | expected delivery, the    | controls. In the         |
|              | rats were killed.         | pregnant rats the        |
|              |                           | formalin treatment       |
|              | Pregnant White Rat -- No  | induced an adaptation    |
|              | Information on Number and | with enlargement of the  |
|              | Type provided             | 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    | **MRID 00164652**         | Maternal Toxicity:       |
|              |                           |                          |
| Prenatal     | Marks, Thomas A. et al.   | **NOAEL = 0 mg/kg/day**  |
|              | (1980) Influence of       |                          |
| D            | Formaldehyde and Sonacide | **LOAEL = 74             |
| evelopmental | (Potentiated Acid         | mg/kg/day**, based on    |
|              | Glutaraldehyde) on Embryo | decreased body weight    |
| Toxicity     | and Fetal Development in  | gain.                    |
| (rodent)     | Mice. Teratology 22:      |                          |
|              | 51-58.                    | The 185 mg/kg/day dose   |
| Purity:      |                           | of formaldehyde was      |
| Fischer      | Oral gavage (76/29/35/34  | clearly toxic; 22 of the |
| certified    | animals/dose) 0, 74, 148, | 34 pregnant mice died    |
| ACS          | or 185 mg/kg/day, GD 6-15 | before day 18. Methanol, |
| solution,    |                           | 12-15% of the original   |
| contains     | Female CD-1 Mice          | solution, may have       |
| 12-15%       |                           | contributed to this      |
| methanol     |                           | 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    | Saillenfait, A.M., et al  | Maternal Toxicity:       |
|              | (1989) The effects of     |                          |
| Prenatal     | maternally inhaled        | **NOAEL = 24.8 mg/m^3^** |
|              | formaldehyde on embryonal |                          |
| D            | and foetal development in | **LOAEL = 49.6           |
| evelopmental | rats. Fd. Chem. Toxic.    | mg/m^3^**, based on      |
|              | 27(8): 545-548.           | decreased body weight    |
| Toxicity     |                           | gain                     |
|              | **Open Literature**       |                          |
| Purity: 37%  |                           | Offspring Toxicity:      |
| a.i.         | Female Sprague-Dawley     |                          |
|              | rats (25/dose)            | **NOAEL = 12.4 mg/m^3^** |
|              |                           |                          |
|              | 0, 5, 10, 20, or 40 ppm   | **LOAEL = 24.8           |
|              | (0, 6.2, 12.4, 24.8, or   | mg/m^3^**, based on      |
|              | 49.6 mg/m^3^) for 6       | reduced fetal            |
|              | hr/day, GD 6-20           |                          |
|              |                           | 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/m^3^ and 21%     |
|              |                           | less at 49.6 mg/m^3^).   |
+--------------+---------------------------+--------------------------+
| 870.3700a    | Overman, D.O. (1984)      | Treatment had no effect  |
|              | Absence of Embryotoxic    | on maternal weight gain. |
| Prenatal     | Effects of Formaldehyde   | The treatment did not    |
|              | after Percutaneous        | influence fetal C- R     |
| D            | Exposure in Hamsters.     | length. Mean fetal       |
| evelopmental | Toxicology Letters 24:    | weight was slightly      |
|              | 107-110.                  | increased in             |
| Toxicity     |                           | experimental animals,    |
| (rodent)     | **Open Literature**       | but the difference was   |
|              |                           | not                      |
| Purity: 37%  | Pregnant Charles river    | st                       |
| a.i.         | Lak:LVG (SYR) Golden      | atistically-significant. |
|              | strain hamsters -- Number | Two fetuses from the     |
|              | of animals not reported   | same litter after        |
|              |                           | treatment on day 8 were  |
|              | 0.5 mL, 2 hours/day, GD   | significantly smaller    |
|              | 8-11                      | 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     | **MRID 00143291**         | The study revealed no    |
|              |                           | teratogenic action.      |
| Reproduction | Hurni, H. and H. Odher    |                          |
| and          | (1972) Reproduction Study | The treatments did not   |
| fertility    | with Formaldehyde and     | affect the pregnancy     |
| effects      | Hexamethylenetetr-amine   | rate. The body weight    |
|              | in Beagle Dogs. Fd.       | increased regularly      |
| Purity: 40%  | Cosmet. Toxicol. 11:      | during pregnancy in all  |
| a.i.         | 459-462.                  | groups and the duration  |
|              |                           | of gestation was         |
|              | 51 female Beagle dogs     | unaffected by the        |
|              |                           | treatments. The mean     |
|              | 0, 3.1, or 9.4 mg/kg/day  | litter size was within   |
|              |                           | the normal range for all |
|              | **Not Reviewed**          | 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     | []{.mark}                 | 200 mg/kg: A             |
|              |                           | statistically            |
| Reproduction | Cassidy, S.L., K.M. Dix,  | significant increase in  |
| and          | and T. Jenkins (1983)     | total sperm heads per    |
| fertility    | Evaluation of a           | gram testis, as well as  |
| effects      | testicular sperm head     | an increase in           |
|              | counting technique using  | percentage of abnormal   |
| Purity: 40%  | rats exposed to           | sperm heads. Data        |
| a.i.         | dimethoxyethyl phthalate  | indicated that \"the     |
|              | (DMEP), glycerol          | induction of increased   |
|              | a-monochlorohydrin        | levels of abnormal sperm |
|              | (GMCH), epichlorohydrin   | may be a measurable      |
|              | (ECH), formaldehyde (FA), | index of the mutagenic   |
|              | or methyl                 | potential of a chemical  |
|              | methanesulphonate (MMS).  | for mammalian germ       |
|              | Arch. Toxicol. 53:71-78   | cells".                  |
|              |                           |                          |
|              | **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      |                          |
+--------------+---------------------------+--------------------------+
| **Chronic    |                           |                          |
| Toxicity**   |                           |                          |
+--------------+---------------------------+--------------------------+
| 870.4100a    | Battelle, Pacific         | Concentrations of 123.93 |
|              | Northwest Laboratories.   | mg/m^3^ or greater       |
| Chronic      | (1980)                    | produced 100% mortality. |
| Toxicity     |                           | The highly irritating    |
|              | \"Tracor Jitco Inhalation | nature of this chemical  |
| Purity:      | Carcinogenesis Bioassay:  | was evident              |
| 9.20%        | Repeated Dose Study       | microscopically in all   |
|              | Report on Formaldehyde.\" | dose levels examined,    |
|              |                           | ranging from minimal to  |
|              | **Open Literature**       | mild supportive rhinitis |
|              |                           | in the 18.59 mg/m^3^     |
|              | B6C3F1 Mouse              | dose level dose level,   |
|              | (5/sex/group)             | to necrosis and          |
|              |                           | sloughing of the mucosa  |
|              | Mice were exposed to one  | in the turbinates,       |
|              | of five concentrations of | trachea, and proximal    |
|              | vaporized formaldehyde    | bronchi in the 61.96     |
|              | for a period of 6 hours   | mg/m^3^ animals.         |
|              | per day for a total of    |                          |
|              | ten exposures. The target | Differential weight      |
|              | concentrations were 15,   | gains of both male and   |
|              | 25, 50, 100, and 200 ppm  | female mice at 18.59,    |
|              | (18.59, 30.98, 61.96,     | 30.98, and 61.96 mg/m^3^ |
|              | 123.93, and 247.85        | was significant as       |
|              | mg/m^3^).                 | compared to the          |
|              |                           | controls. At 123.93 and  |
|              |                           | 247.85 mg/m^3^, only     |
|              |                           | female mice showed       |
|              |                           | significant weight loss, |
|              |                           | as the early mortality   |
|              |                           | of the males precluded   |
|              |                           | obtaining any meaningful |
|              |                           | data.                    |
+--------------+---------------------------+--------------------------+
| 870.4100a    | Kamata, Eiichi et al.     | **NOAEL: 0.4 mg/m^3^**   |
|              | (1997) Results of a       |                          |
| Chronic      | 28-month Chronic          | **LOAEL: 2.5 mg/m^3^**   |
| Toxicity     | Inhalation Toxicity Study |                          |
|              | of Formaldehyde in Male   | Nasal tumors were        |
| Purity: 37%  | Fischer-344 Rats. The     | macroscopically evident  |
| a.i.         | Journal of Toxicological  | in the 19 mg/m^3^ group  |
|              | Sciences 22(3): 239-254.  | from the 14th month.     |
|              |                           | Histopathological        |
|              | **Open Literature**       | examination revealed     |
|              |                           | squamous cell papillomas |
|              | Male Fischer 344 rats     | and carcinomas. No nasal |
|              | (32/dose)                 | tumors were observed in  |
|              |                           | the lower exposure       |
|              | 0, 0.3, 2, or 15 ppm (0,  | groups (0.4 and 2.5      |
|              | 0.4, 2.5, or 19 mg/m^3^), | mg/m^3^ groups). In the  |
|              | 6hr/day, 5 days/week via  | high-dose group,         |
|              | inhalation                | 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/m^3^ 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/m^3^, respectively.   |
+--------------+---------------------------+--------------------------+
| **Carci      |                           |                          |
| nogenicity** |                           |                          |
+--------------+---------------------------+--------------------------+
| 870.4200a    | **MRID 00143288**         | 0.6% to 0.8%: necrosis,  |
|              |                           | the formation of an      |
| Oncogenicity | Watanabe, F., et al.      | ulcer, while the area    |
| (Rat)        | (1954) Study on the       | around the injection     |
|              | Carcinogenicity of        | spot formed a tuber      |
|              | Aldehyde. 1st Report.     | which was very difficult |
|              | Experimentally Produced   | to heal                  |
|              | Rat Sarcomas by Repeated  |                          |
|              | Injections of Aqueous     | 0.4% - 0.5%: rare        |
|              | Solution of Formaldehyde. | occurrence of an ulcer.  |
|              | Two unpublished           | After two to five months |
|              | translations of Japanese  | after having stopped the |
|              | article published in Gann | injections observations  |
|              | 45(2-3):451-452.          | revealed the occurrence  |
|              |                           | of sarcomas either at    |
|              | Rat                       | the injection spot or in |
|              |                           | the internal organs of 4 |
|              | Repeated subcutaneous     | out of 10 of the rats.   |
|              | 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.    |                          |
+--------------+---------------------------+--------------------------+
| 870.4200a    | Tobe, M., T. Kaneko, Y.   | During the exposure      |
|              | Uchida, et al. 1985.      | running noses, running   |
| Oncogenicity | Studies of the inhalation | tears and crouching were |
| (Rat)        | toxicity of formaldehyde. | seen in the 15 ppm dose  |
|              | National Sanitary and     | group. These symptoms    |
|              | Medical Laboratory        | decreased as the number  |
|              | Service (Japan). p. 1-94. | of exposures increased.  |
|              |                           | Hair around the          |
|              | []{.mark}                 | abdominal region was     |
|              |                           | observed to be yellow in |
|              | **Open Literature**       | color and bleeding from  |
|              |                           | the forelimbs was seen.  |
|              | []{.mark}                 | Yellow discoloration of  |
|              |                           | abdominal hair was also  |
|              | 32 Male Fischer 344       | seen in the 2.0 ppm dose |
|              | rats/dose                 | group although it was    |
|              |                           | light. Significant       |
|              | []{.mark}                 | suppression of weight    |
|              |                           | gain and a decrease in   |
|              | Test material was         | the amount of food gain  |
|              | administered at           | were seen in the 15 ppm  |
|              | concentrations of 0, 0.3, | dose group. 20 of 24     |
|              | 2.0 or 15 ppm in aqueous  | animals in the 15 ppm    |
|              | solution methanol, 6      | dose group died in the   |
|              | hours/day, 5 days/week    | 24 month dosing period   |
|              | for 28 months. The        | giving a high death rate |
|              | exposure at 15 ppm was    | of 88.3%.                |
|              | tested for 24 months. A   |                          |
|              | positive control -- 3.3   | Recognizable tumors were |
|              | ppm methanol and a        | observed in the 15 ppm   |
|              | nonexposure (NE) control  | group from the 420^th^   |
|              | were also used.           | day onwards and tumors   |
|              |                           | were recognized          |
|              | []{.mark}                 | macroscopically in eight |
|              |                           | animals by the 24^th^    |
|              |                           | 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  |
|              |                           | 825^th^ 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    | Takahashi et al. (1986)   | Formalin did not produce |
|              | Effects of Ethanol,       | malignant tumors when    |
| Oncogenicity | Potassium Metabisulfate,  | given alone. Forestomach |
| (Rat)        | Formaldehyde, and         | papillomas occurred in   |
|              | Hydrogen Peroxide on      | 8/10 animals             |
|              | Gastric Carcinogenesis in | administered formalin    |
|              | Rats after Initiation     | alone.                   |
|              | with N-                   |                          |
|              | methyl-N\'n               | In the group             |
|              | itro-N\'nitrosoguanidine. | administered both MNG    |
|              | Jap. J. Cancer Res. 77:   | and formalin,            |
|              | 118-124.                  | forestomach papillomas   |
|              |                           | occurred in 15/17        |
|              | **Open Literature**       | animals, adenocarcinoma  |
|              |                           | of the pylorus in 4/17,  |
|              | Male Wistar rats          | preneoplastic            |
|              |                           | hyperplasia of the       |
|              | A two-stage               | pylorus in 7/17, and     |
|              | carcinogenesis bioassay   | adenocarcinoma of the    |
|              | was conducted in which    | duodenum in 1/17.        |
|              | 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).               |                          |
+--------------+---------------------------+--------------------------+
| 870.4200b    | Iversen, Olav Hilmar.     | Nonspecific granulomas   |
|              | (1986) Formaldehyde and   | in the lung; slight      |
| Oncogenicity | Skin Carcinogenesis.      | hyerplasia of the        |
|              | Environ Int 12:541-544.   | epidermis, small skin    |
| (Mouse)      |                           | ulcers                   |
|              | **Open Literature**       |                          |
| Purity: 1%   |                           |                          |
| and 10%      | 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 |                          |
+--------------+---------------------------+--------------------------+
| 870.4200b    | Krivanek, N.D., N.C.      | Repeated doses of 2-5 mg |
|              | Chromey and J.W. McAlack, | caused mild to moderate  |
| Oncogenicity | \"Skin initiation-        | skin irritation, whereas |
|              | promotion study with      | 1 mg caused only mild    |
| (Mouse)      | formaldehyde in CD-1      | irritation.              |
|              | mice\", E.I. du Pont de   |                          |
| Purity: 10%  | Nemours & Company, Inc.   | As expected, BaP/TPA     |
|              | In: Formaldehyde:         | gave a high tumor yield  |
|              | Toxicology, Epidemiology, | (28/29 mice, 9 of which  |
|              | and Mechanisms, Clary,    | had malignant tumors.    |
|              | J.J., J.E. Gibson, and    | Benign test site tumors  |
|              | R.S. Waritz, Eds., N.Y.,  | were keratoacanthomas or |
|              | Marcel Dekker, Inc.,      | squamous papillomas. No  |
|              | 1983.                     | other combinations gave  |
|              |                           | yields significantly     |
|              | **Open Literature**       | different from controls. |
|              |                           | Thus the test is         |
|              | Female CD-1 Mouse         | negative under study     |
|              |                           | conditions, with the     |
|              | Mice were treated on      | caveat that one cannot   |
|              | shaved dorsal skin with   | be certain whether       |
|              | up to 10 mg formaldehyde, | formaldehyde underwent   |
|              | followed by repeated      | significant degradation  |
|              | doses. Formaldehyde was   | to formic acid or other  |
|              | also applied once at 5    | products.                |
|              | 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 \[150   |                          |
|              | mg benzo(a)pyrene (BaP)   |                          |
|              | as initiator, 2.5 mg      |                          |
|              | 12-O-                     |                          |
|              | tetradecano               |                          |
|              | ylphorbol-13-acetate(TPA) |                          |
|              | as promoter\], or         |                          |
|              | negative control          |                          |
|              | (acetone) were used.      |                          |
+--------------+---------------------------+--------------------------+
| 870.4200b    | Spangler, F. and J.M.     | Study found no evidence  |
|              | Ward, \"Skin              | of formaldehyde as an    |
| Oncogenicity | initiation/promotion      | initiating agent, nor as |
|              | study with formaldehyde   | a complete carcinogen,   |
| (Mouse)      | in Sencar mice\". Study   | however investigators    |
|              | location: Microbiological | considered there to be   |
|              | Associates (Bethesda, MD) | \"a slight possibility   |
|              | in conjunction with NCI.  | that formaldehyde may be |
|              | In: Formaldehyde:         | a very, very weak        |
|              | Toxicology, Epidemiology, | promoting agent\", based |
|              | and Mechanisms, Clary,    | on a very small tumor    |
|              | J.J., J.E. Gibson, and    | yield when formaldehyde  |
|              | R.S. Waritz, Eds., N.Y.,  | was tested as a promoter |
|              | Marcel Dekker, Inc.,      | in mice treated with     |
|              | 1983.                     | DMBA.                    |
|              |                           |                          |
|              | **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.                    |                          |
+--------------+---------------------------+--------------------------+
| 870.4200     | Dalbey, W.E. (1982).      | Lifetime exposure to     |
|              | Formaldehyde and tumors   | formaldehyde reduced     |
| Oncogenicity | in hamster respiratory    | survival time (*P* \<    |
|              | tract. Toxicology. 24:    | 0.05) relative to        |
|              | 9-14.                     | unexposed controls. No   |
|              |                           | tumors were observed in  |
|              | **Open Literature**       | the respiratory tract of |
|              |                           | non-exposed hamsters or  |
|              | 88 male Syrian golden     | of those exposed to      |
|              | hamsters                  | formaldehyde. There was, |
|              |                           | therefore, no evidence   |
|              | Test material was         | of carcinogenic activity |
|              | administered at a 10 ppm  | of formaldehyde under    |
|              | concentration 5           | the given exposure       |
|              | times/week for lifetime.  | 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     | **MRID 00143289**         | From exposure weeks 3 to |
|              |                           | 103, mildly (15 to35 g)  |
| Chronic/     | Kerns, W.D. et al. (1983) | decreased body weights   |
| Oncogenicity | Carcinogenicity of        | (p\<0.05) in male and    |
|              | Formaldehyde in Rats and  | female rats (6.9 and 18  |
|              | Mice after Long-Term      | mg/m^3^) were observed.  |
|              | Inhalation Exposure.      | Animals in the 2.5       |
|              | Cancer Research 43:       | mg/m^3^ exposure group   |
|              | 4382-4392.                | had sporadically reduced |
|              |                           | body weights (p\>0.05)   |
|              | Rat (Fischer 344) and     | throughout the exposure  |
|              | Mice (B6C3F~1~) - approx  | period. Male and female  |
|              | 120/sex/dose              | rats in the 18 mg/m3     |
|              |                           | exposure group exhibited |
|              | 0, 2.0, 5.6, or 14.3 ppm  | significantly increased  |
|              | (0, 2.5, 6.9, or 18       | mortality (p\<0.001)     |
|              | mg/m^3^), 6 hrs/day, 5    | from the 12th month      |
|              | days/week, up to 24       | onward. Male rats in the |
|              | months                    | intermediate exposure    |
|              |                           | groups showed a          |
|              |                           | s                        |
|              |                           | tatistically-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/m^3^ 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/m^3^       |
|              |                           | 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/m^3^   |
|              |                           | 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/m^3^. 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/m^3^ 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/m^3^.                 |
+--------------+---------------------------+--------------------------+
| **Neu        |                           |                          |
| rotoxicity** |                           |                          |
+--------------+---------------------------+--------------------------+
| 870.6200     | Malek, FA; Moritz, KU;    | Malek et al. (2003a):    |
|              | Fanghanel, J. (2003a)     |                          |
| N            | Formaldehyde inhalation   | **LOAEL = 1.0 ppm, 2     |
| eurotoxicity | and open field behaviour  | hours**                  |
| screening    | in rats. Ind J Med Res    |                          |
| battery      | 118:90-96.                | In general, sniffing was |
|              |                           | increased after          |
| Purity:      | Malek, FA; Moritz, K-U;   | formaldehyde exposure    |
|              | Fanghaenel, J. (2003b) A  | and movement was         |
| (2003a) -    | study on specific         | decreased (crossed       |
| 37% stock    | behavioral effects of     | quadrants and climbing)  |
| solution was | formaldehyde in the rat.  | in both male and female  |
| used to      | J Exp Anim Sci            | rats (p\<0.05).          |
| prepare      | 42:160-170.               | Significant reductions   |
| solutions of |                           | in horizontal movements  |
| 0.5%, 1%,    | **Open Literature**       | (crossed quadrants) were |
| and 2.5%     |                           | observed at all dose     |
|              | Male and Female LEW.1K    | levels and were          |
| (2003b) --   | Rat                       | characterized by a       |
| 0.1%, 0.2%,  |                           | U-shaped dose response.  |
| and 1%       | Malek et al. (2003a):     | The lowest dose tested   |
|              | Rats were exposed to 0,   | (1 ppm) demonstrated     |
|              | 1.0, 2.5, or 5.0 ppm (0,  | higher level of activity |
|              | 1.23, 3.08, or 6.15       | suppression than the two |
|              | mg/m^3^) formaldehyde for | higher doses, but all    |
|              | 2 hours. Mean             | groups were still        |
|              | formaldehyde levels of    | suppressed relative to   |
|              | 1.01 ± 0.29 ppm, 2.51 ppm | controls. Although       |
|              | (standard deviation is    | female rats displayed a  |
|              | missing) and 5.04 ± 0.27  | greater level of         |
|              | ppm were achieved.        | activity overall, a      |
|              | Locomotor activity was    | similar U-shaped         |
|              | assessed for 1 hour in an | dose-response pattern    |
|              | open field 2 and 24 hours | was also observed.       |
|              | after termination of      |                          |
|              | formaldehyde exposure.    | After 24 hours, as       |
|              |                           | expected, controls       |
|              | Malek et al. (2003b):     | demonstrated habituation |
|              | Rats (10 per group) were  | to the test apparatus    |
|              | exposed at 0, 0.1, 0.5,   | exhibiting only 20% of   |
|              | or 5.0 ppm (0, 0.123,     | the motor activity       |
|              | 0.615, or 6.15 mg/m^3^)   | observed on day 1. In    |
|              | formaldehyde for 2 hours. | contrast,                |
|              | Open field behavior tests | formaldehyde-treated     |
|              | were conducted on each    | animals failed to        |
|              | animal 2 hours after      | demonstrate the same     |
|              | formaldehyde exposure.    | 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     | Pitten, FA; Kramer, A;    | **LOAEL: 2.6 ppm, 10     |
|              | Herrmann, K; et al.       | min/90 days**            |
| Schedul      | (2000) Formaldehyde       |                          |
| e-controlled | neurotoxicity in animal   | The authors reported     |
| operant      | experiments. Pathol Res   | that no gender           |
| behavior     | Pract 196:193-198.        | differences existed as a |
|              |                           | function of formaldehyde |
|              | **Open Literature**       | treatment; therefore,    |
|              |                           | data were presented by   |
|              | Adult Male and Female     | combining sexes. Control |
|              | Wistar Rat (5 to          | rats showed no change in |
|              | 8/sex/group)              | error rate but a slight  |
|              |                           | decrease in running time |
|              | Pitten et al. (2000)      | through the maze during  |
|              | evaluated the effects of  | the course of the        |
|              | very brief formaldehyde   | experiment. The          |
|              | exposures (10 minutes)    | formaldehyde-exposed     |
|              | but prolonged duration    | groups began with a      |
|              | (90 days) on previously   | similar performance      |
|              | learned performance in a  | level and error rate as  |
|              | land version of the       | controls, but their      |
|              | labyrinth maze. Rats were | performance degraded     |
|              | acclimated to the task    | over the course of       |
|              | for 14 days, 2            | formaldehyde exposure.   |
|              | trials/day. Animals were  | By the fourth week of    |
|              | required to make a series | exposure, increased      |
|              | of five consecutive turns | numbers of errors were   |
|              | from the entrance of the  | evident in both exposed  |
|              | maze to retrieve a piece  | groups relative to       |
|              | of cheese placed in the   | controls. This trend     |
|              | goal box at the opposite  | reached statistical      |
|              | end. Animals were exposed | significance by the      |
|              | to 0 ppm, 2.6 ppm (0.25%  | thirteenth week for a    |
|              | formaldehyde solution to  | greater than twofold     |
|              | yield 3.06 ± 0.77 mg/m3   | increase in error rate   |
|              | ), or 4.6 ppm (0.70%      | (p\<0.05).               |
|              | formaldehyde solution to  | Formaldehyde-treated     |
|              | yield 5.55 ± 1.27 mg/m3)  | rats also tended to have |
|              | formaldehyde, 10          | increased run times      |
|              | minutes/day, 7 days/week  | through the maze         |
|              | for 90 days. Animals were | (p=0.04), but no         |
|              | assessed for performance  | difference was seen by   |
|              | in the maze every seventh | formaldehyde             |
|              | day, at least 22 hours    | concentration. By 4      |
|              | after the exposure on the | weeks after termination  |
|              | previous day. At the end  | of exposure, no          |
|              | of the 90-day exposure    | statistical differences  |
|              | period, monitoring of     | among the three groups   |
|              | maze performance          | were evident, but the    |
|              | continued once every 10   | tendency for the two     |
|              | days for an additional 40 | exposed groups to make   |
|              | days.                     | 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        | Boja JW, Nielsen JA,      | Exposure to 6.20 mg/m^3^ |
|              | Foldvary E, et al. (1985) | formaldehyde resulted in |
| Purity: 96%  | Acute Low-Level           | statistically            |
|              | Formaldehyde Behavioural  | significant decreased    |
|              | and Neurochemical         | motor activity within 15 |
|              | Toxicity in the Rat. Prog | minutes. At the          |
|              | Neuro-Psychopharmacol     | beginning of day 2, all  |
|              | Biol Psychiat 9:671-674.  | of the rats exposed to   |
|              |                           | formaldehyde on day 1    |
|              | **Open Literature**       | displayed lower activity |
|              |                           | levels. Similar effects  |
|              | 88 M Sprague-Dawley Rat   | on motor activity were   |
|              |                           | seen at the 12.39        |
|              | Rats were exposed to      | mg/m^3^ formaldehyde     |
|              | either air or             | exposure level, whereas  |
|              | formaldehyde at           | effects seen after 24.79 |
|              | concentrations of 5, 10,  | mg/m^3^ exposure were    |
|              | or 20 ppm (6.20, 12.39,   | reported to be "not      |
|              | or 24.79 mg/m^3^) via     | readily interpretable"   |
|              | inhalation for 3 hours on | and were not shown.      |
|              | two days                  | Exposure to 6.20 mg/m^3^ |
|              |                           | formaldehyde             |
|              |                           | statistically            |
|              |                           | significantly increased  |
|              |                           | concentrations of        |
|              |                           | 5-hydroxyindoleacetic    |
|              |                           | acid,                    |
|              |                           | 3                        |
|              |                           | ,4-dihydroxyphenylacetic |
|              |                           | acid, and dopamine in    |
|              |                           | the hypothalamus.        |
+--------------+---------------------------+--------------------------+
| **           |                           |                          |
| Metabolism** |                           |                          |
+--------------+---------------------------+--------------------------+
|              |                           |                          |
+--------------+---------------------------+--------------------------+
| 870.7485     | Casanova, Mercedes,       | DNA-protein crosslinking |
|              | Donald F. Deyom and Henry | occurred at all          |
| General      | D\'A. Heck (1989)         | concentrations. The      |
| Metabolism   | Covalent Binding of       | formation of crosslinks  |
|              | Inhaled Formaldehyde to   | was interpreted in terms |
|              | DNA in the Nasal Mucosa   | of a nonlinear           |
|              | of Fischer 344 Rats:      | pharmacokinetic model    |
|              | Analysis of Formaldehyde  | incorporating oxidation  |
|              | and DNA by                | of inhaled formaldehyde  |
|              | High-Performance Liquid   | as a defense mechanism.  |
|              | Chromatography and        | The slope of the fitted  |
|              | Provisional               | concentration-response   |
|              | Pharmacokinetic           | curve at 12 mg/m^3^      |
|              | Interpretation.           | is7.3-fold greater than  |
|              | Fundamental and Applied   | at 0.37 mg/m^3^, and the |
|              | Toxicology 12: 397-417.   | detoxification pathway   |
|              |                           | is half-saturated at an  |
|              | **Open Literature**       | airborne concentration   |
|              |                           | of 3.2 mg/m^3^.          |
|              | 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/m^3^) for 6 |                          |
|              | hours                     |                          |
+--------------+---------------------------+--------------------------+
| 870.7485     | Casanova-Schmitz,         | The major route of       |
|              | Mercedes, Thomas B.       | nucleic acid labeling at |
| General      | Starr, and Henry D\'A.    | all concentrations and   |
| Metabolism   | Heck (1984)               | in all tissues was       |
|              | Differentiation between   | metabolic incorporation; |
|              | Metabolic Incorporation   | protein labeling in the  |
|              | and Covalent Binding in   | respiratory mucosa was   |
|              | the Labeling of           | mainly due to covalent   |
|              | Macromolecules in the Rat | binding at the higher    |
|              | Nasal Mucosa and Bone     | formaldehyde             |
|              | Marrow by Inhaled (14C)-  | concentration.           |
|              | and (3H) Formaldehyde.    | Incorporation of 14C-    |
|              | Toxicology and Applied    | formaldehyde into DNA in |
|              | Pharmacology 76: 26-44.   | the respiratory mucosa   |
|              |                           | was maximal at 7.4       |
|              | **Open Literature**       | mg/m^3^ but decreased at |
|              |                           | higher concentrations,   |
|              | Rats (4/group)            | whereas labeling of DNA  |
|              |                           | in the olfactory mucosa  |
|              | 14C and 3H- formaldehyde  | and bone marrow          |
|              | was administered at doses | increased monotonically  |
|              | of 0, 0.3, 2, 6, 10, or   | with concentration.      |
|              | 15 ppm (0, 0.37, 2.5,     | Evidence for covalent    |
|              | 7.4, 12, or 19 mg/m^3^)   | binding of formaldehyde  |
|              | for 6 hours               | to respiratory mucosal   |
|              |                           | DNA was obtained at      |
|              |                           | formaldehyde             |
|              |                           | concentrations equal to  |
|              |                           | or greater than 2.5      |
|              |                           | mg/m^3^. The             |
|              |                           | concentration of         |
|              |                           | formaldehyde covalently  |
|              |                           | bound to DNA at 7.4      |
|              |                           | mg/m^3^ was 10.5-fold    |
|              |                           | higher than at 2.5       |
|              |                           | mg/m^3^, 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.      | The analysis suggested   |
|              | 2003. Biologically        | evidence of: 1) a        |
|              | Motivated Computational   | cy                       |
|              | Modeling of Formaldehyde  | tolethality-regenerative |
|              |                           | cellular proliferation   |
|              | Carcinogenicity in the    | (CRCP) mechanism with    |
|              | F344 Rat. Toxicol. Sci.   | little or no involvement |
|              | 75: 432--447.             | of direct mutagenesis;   |
|              |                           | and 2) a J-shaped        |
|              | **Open Literature**       | dose-response            |
|              |                           | relationship between     |
|              | 3-D F344 Rat Model        | formaldehyde and         |
|              |                           | squamous cell carcinoma. |
|              | 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.              |                          |
+--------------+---------------------------+--------------------------+
| S            | Ohtsuka, R; Shuto, Y;     | Although no pulmonary    |
| ensitization | Fujie, H; et al. (1997)   | measurements were made,  |
|              | Response of respiratory   | the authors observed     |
|              | epithelium of BN and F344 | fewer clinical signs of  |
|              | rats to formaldehyde      | respiratory irritation   |
|              | inhalation. Exp Anim      | in the BN rats compared  |
|              | 46:279-286.               | to F344 rats, such as    |
|              |                           | abnormal respiration     |
|              | Ohtsuka, R; Shutoh, Y;    | (three versus five) and  |
|              | Fujie, H; et al. (2003)   | nasal discharge (three   |
|              | Rat strain difference in  | versus five).            |
|              | histology and expression  | Formaldehyde-treated     |
|              | of Th1- and Th2-related   | F344 rats showed less    |
|              | cytokines in nasal mucosa | body weight gain over    |
|              | after short-term          | the 2-week treatment,    |
|              | formaldehyde inhalation.  | resulting in lower body  |
|              | Exp Toxicol Pathol        | weight at week 1 and     |
|              | 54:287-291.               | week 2 than F344         |
|              |                           | controls (p\<0.05 and    |
|              | **Open Literature**       | 0.01). BN rats were more |
|              |                           | resistant to epithelial  |
|              | 18 F344 and 18 Brown      | cell damage than F344    |
|              | Norway (BN) Rats          | rats, exhibiting milder  |
|              |                           | lesions that impacted a  |
|              | []{.mark}                 | smaller portion of the   |
|              |                           | URT. Squamous            |
|              | Rats were exposed to      | metaplasias were present |
|              | formaldehyde aerosol for  | in the respiratory       |
|              | 3 hours/day, 5 days/week  | epithelium (Levels 1 and |
|              | for 2 weeks. The aerosol  | 2) in both strains in    |
|              | was generated from a 1%   | formaldehyde-treated     |
|              | formaldehyde solution by  | rats. However, a         |
|              | a two-fluid atomizer and  | distinct keratinized     |
|              | formaldehyde level        | layer was noted in Level |
|              | maintained at 2 mg (1%    | 1 epithelium of F344     |
|              | sol.)/L (approximately 16 | rats, and the extent of  |
|              | ppm or 20 mg/m^3^), by    | lesions in Level 2       |
|              | adjusting the flow rate   | respiratory epithelium   |
|              | for formaldehyde solution | was much greater than    |
|              | to the atomizer.          | that seen in BN rats.    |
|              |                           | Additionally, the        |
|              | []{.mark}                 | 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/m^3^).                |
|              |                           |                          |
|              |                           | 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.        |
+--------------+---------------------------+--------------------------+
| S            | Biagini, RE; Moorman, WJ; | Methacholine challenge   |
| ensitization | Knecht, EA; et al. (1989) | increased pulmonary flow |
|              | Acute airway narrowing in | resistance at increasing |
| Purity: 37%  | monkeys from challenge    | levels of methacholine   |
| formalin     | with 2.5 ppm formaldehyde | (0.125, 0.5, 2.0, and    |
|              | generated from formalin.  | 8.0 mg/mL) to 196 ± 16,  |
|              | Arch Environ Health       | 285 ± 57, 317 ± 64, and  |
|              | 44:12-17.                 | 461 ± 120 % of baseline  |
|              |                           | levels respectively.     |
|              | **Open Literature**       | Similarly, formaldehyde  |
|              |                           | exposure increased       |
|              | 9 Cynomolgus Monkeys      | pulmonary flow           |
|              | known to be hyperreactive | resistance from 11.3 ±   |
|              | to methacholine           | 1.4 cm H2O prior to      |
|              | (acetyl-β-methacholine    | formaldehyde exposure,   |
|              | chloride)                 | to 16.1 ± 2.1, 16.9 ±    |
|              |                           | 2.8, and 20.0 ± 3.4 cm   |
|              | The effect of a single    | H2O, at 2, 5, and 10     |
|              | pulmonary exposure on     | minutes after            |
|              | pulmonary mechanics       | formaldehyde exposure    |
|              | including bronchial       | (with 142, 150, and 177% |
|              | constriction (BC) was     | change, respectively).   |
|              | evaluated. Each monkey    | Although bronchial       |
|              | was exposed separately to | constriction, seen as    |
|              | methacholine and          | increased pulmonary flow |
|              | formaldehyde in order to  | resistance, was          |
|              | compare their             | increased by both        |
|              | formaldehyde response to  | methacholine and         |
|              | an agent known to trigger | formaldehyde, there was  |
|              | BC. Monkeys were exposed  | not a correlation        |
|              | to increasing levels of   | between methacholine     |
|              | methacholine for 10       | responsiveness and the   |
|              | minutes (0, 0.125, 0.5,   | magnitude of effect      |
|              | 2.0, and 8.0 mg/mL) as an | after formaldehyde       |
|              | aerosol (0.065 mL/min     | exposure (p\>0.1).       |
|              | with a mean aerodynamic   | Therefore although       |
|              | diameter of 1.0-1.5 μm).  | formaldehyde exposure    |
|              | After a 2-week recovery   | stimulated BC similarly  |
|              | period, pulmonary         | to a known direct        |
|              | mechanics were measured   | stimulating agent,       |
|              | before and after a        | formaldehyde may not     |
|              | 10-minute exposure to 2.5 | work through the same    |
|              | ppm formaldehyde (2, 5,   | site of action as        |
|              | and 10 minutes            | methacholine.            |
|              | post-exposure).           |                          |
+--------------+---------------------------+--------------------------+
| S            | Fujimaki, H; Kurokawa, Y; | In nonimmunized mice,    |
| ensitization | Kunugita, N; et al.       | spleen weights were      |
|              | (2004) Differential       | reduced by formaldehyde  |
|              | immunogenic and           | exposure from 152 mg in  |
|              | neurogenic inflammatory   | control to 128, 118, and |
|              | responses in an allergic  | 121 mg in mice exposed   |
|              | mouse model exposed to    | to 0.08, 0.40, and 1.8   |
|              | low levels of             | ppm formaldehyde,        |
|              | formaldehyde. Toxicology  | respectively. However,   |
|              | 197:1-13.                 | spleen weights were      |
|              |                           | unchanged by             |
|              | **Open Literature**       | formaldehyde exposure in |
|              |                           | OVA-immunized mice. In   |
|              | Mice were exposed to 0,   | immunized mice exposed   |
|              | 0.082, 0.393, or 1.87 ppm | to 1.8 ppm formaldehyde, |
|              | formaldehyde (0, 0.1,     | the total number of BAL  |
|              | 0.48, or 2.3 mg/m^3^), 16 | cells, MPs, and          |
|              | hours/day, 5 days/week    | eosinophils were         |
|              | for 12 weeks. Six mice at | increased (9.65 versus   |
|              | each exposure level were  | 2.84, 7.22 versus 2.74,  |
|              | given intraperitoneal     | and 2.0 versus 0.02 ×104 |
|              | injections of OVA plus    | cells, respectively).    |
|              | adjuvant before the       |                          |
|              | initial exposure and on   | Levels of IL-1β in BAL   |
|              | weeks 3, 6, 9, and 11 of  | of immunized mice were   |
|              | the experiment. Five mice | decreased by             |
|              | at each                   | formaldehyde exposure    |
|              | formaldehyde-exposure     | (p\<0.05 at 1.8 ppm      |
|              | level did not receive OVA | formaldehyde).           |
|              | injections. One day after | Immunization with OVA    |
|              | the last exposure,        | significantly increased  |
|              | spleens were collected    | the neuropeptide nerve   |
|              | and disaggregated and     | growth factor (NGF) in   |
|              | spleen cells harvested    | BAL. However, this       |
|              | for cell culture.         | increase with OVA        |
|              | Lymphocyte proliferation  | immunization was         |
|              | in response to            | attenuated by 0.08 and   |
|              | lipopolysaccharide (LPS), | 0.40 ppm formaldehyde    |
|              | phytohemagglutinin A      | exposure. A similar      |
|              | (PHA), or OVA was         | response was seen in     |
|              | determined after 72 hours | blood plasma NGF levels, |
|              | in culture. Splenocytes   | where the increase with  |
|              | were cultured for 48      | OVA immunization was     |
|              | hours in the presence of  | attenuated in mice       |
|              | LPS, PHA, and OVA         | exposed to 0.08 and 0.40 |
|              | (immunized mice only),    | but not to 1.8 ppm       |
|              | and supernatants were     | formaldehyde. Plasma     |
|              | collected for cytokine    | level of Substance P (a  |
|              | analysis (IL-4, IL-5, and | mediator of neurogenic   |
|              | INF-γ). Splenocytes were  | inflammation) was        |
|              | cultured for 24 hours in  | increased by             |
|              | the presence or absence   | formaldehyde exposures   |
|              | of OVA to assess          | in non-immunized mice.   |
|              | chemokine production      | Although Substance P was |
|              | (MCP-1 and MIP1-α).       | increased by OVA         |
|              | Anti-OVA IgE, IgG1, IgG2, | immunization, this again |
|              | and IgG3 were quantified  | seemed to be attenuated  |
|              | in blood plasma.          | 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    | **MRID 43167201**         | Formaldehyde did not     |
| Hype         |                           | cause increased          |
| rsensitivity | Burleigh- Flayer, H. D.   | respiratory rate or      |
|              | and W.J. Kintigh (1992)   | altered respiratory      |
|              | Glutaraldehyde and        | waveform indicative of   |
|              | Formaldehyde: Vapor       | pulmonary                |
|              | Pulmonary                 | hypersensitivity during  |
|              | Hypersensitivity Study in | the challenge exposures. |
|              | Guinea Pigs. Bushy Run    | No mortality, clinical   |
|              | Research Center (Export,  | signs, body weight       |
|              | PA), Union Carbide. Study | effects, or gross        |
|              | ID 92U1123, dated         | lesions were observed    |
|              | February 28, 1992,        |                          |
|              | Unpublished.              |                          |
|              |                           |                          |
|              | **Minimum**               |                          |
|              |                           |                          |
|              | Guinea Pig (8/group)      |                          |
|              |                           |                          |
|              | Induction: 14 ppm (17     |                          |
|              | mg/m^3^), 60 minutes, 5   |                          |
|              | consecutive days          |                          |
|              | Challenge: 5 ppm (6.2     |                          |
|              | mg/m^3^) for 60 minutes,  |                          |
|              | at days 14, 21, and 35    |                          |
|              | following induction       |                          |
+--------------+---------------------------+--------------------------+
| 870.1300     | Dean et al. (1984)        | Decrease in the absolute |
|              | Studies of Immune         | number of monocytes. In  |
| Acute        | Function and Host         | the absence of a         |
| Inhalation   | Resistance in B6C3F1 Mice | difference in recovery   |
| Toxicity     | Exposed to Formaldehyde.  | of peritoneal cells, the |
|              | Toxicology and Applied    | change in monocyte       |
| Purity: 95%  | Pharmacology, v.72, p.    | number may signal only a |
|              | 519-529.                  | peripheral response to   |
|              |                           | the local nasal          |
|              | **Open Literature**       | inflammation and healing |
|              |                           | which occurs following   |
|              | 255 Female (SPF) B6C3F1   | HCHO exposure.           |
|              | Mice                      |                          |
|              |                           |                          |
|              | 21-Day (6 hr/day, 5       |                          |
|              | days/week) inhalation     |                          |
|              | exposure to 18.59 mg/m^3^ |                          |
|              | formaldehyde to test a    |                          |
|              | series of immune function |                          |
|              | and host resistance       |                          |
|              | parameters.               |                          |
+--------------+---------------------------+--------------------------+
| Inhalation   | Casanova, Mercedes, et    | DNA protein cross-links  |
|              | al. (1991) Covalent       | were formed in the       |
|              | Binding of Inhaled        | respiratory tract of     |
|              | Formaldehyde to DNA in    | rhesus monkeys exposed   |
|              | the Respiratory Tract of  | to formaldehyde.         |
|              | Rhesus Monkeys:           | Concentrations of        |
|              | Pharmacokinetics, Rat-    | cross-links (pmol/mg     |
|              | to-Monkey Interspecies    | DNA) were highest in the |
|              | Scaling, and              | mucosa of the middle     |
|              | Extrapolation to Man.     | turbinates; lower        |
|              | Fundamental and Applied   | concentrations were      |
|              | Toxicology 17: 409-428.   | produced in the anterior |
|              |                           | lateral wall/septum and  |
|              | **Open Literature**       | nasopharynx. Very low    |
|              |                           | concentrations were      |
|              | 9 Male Rhesus Monkey      | found in the             |
|              | (*Macaca mulatta*)        | larynx/trachea/carina    |
|              |                           | and in the proximal      |
|              | 14C-Formaldehyde was      | portions of the major    |
|              | administered at 0, 0.7,   | bronchi of some monkeys  |
|              | 2, or 6 ppm (0, 0.87,     | exposed to 7.4 mg/m^3^   |
|              | 2.5, or 7.4 mg/m^3^) for  | but not to 9.87 mg/m^3^. |
|              | 6 hours                   | 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    | Isotopic effect on       |
|              | Merccedes Casanova (1987) | DNA-protein crosslinking |
|              | Isotope Effects and Their | by 3HCHO and H-14-CHO:   |
|              | Implications for the      |                          |
|              | Covalent Binding of       | A small (3.4 +- 0.9%)    |
|              | Inhaled (3H) and (14C)    | isotope effect was       |
|              | Formaldehyde in the Rat   | detected on this         |
|              | Nasal Mucosa. Toxicology  | reaction, which slightly |
|              | and Applied Pharmacology  | favored 3HCHO over       |
|              | 89: 122-134.              | H14CHO in binding to     |
|              |                           | DNA. The magnitude of    |
|              | **Open Literature**       | this isotope effect      |
|              |                           | cannot account for the   |
|              | Male F-344 (CDF/ CrIBR)   | high isotope ratio       |
|              | rats                      | observed in the          |
|              |                           | crosslinked DNA in vivo. |
|              | Isotopic effect on        |                          |
|              | DNA-protein crosslinking  | Isotopic effect on the   |
|              | by 3HCHO and H-14-CHO:    | oxidation of 3HCHO and   |
|              | Rat hepatic nuclei        | H14-CHO:                 |
|              | incubated with 3H and 14C |                          |
|              | formaldehyde              | 3HCHO is oxidized        |
|              |                           | significantly more       |
|              | Isotopic effect on the    | slowly than H14CHO under |
|              | oxidation of 3HCHO and    | these conditions. A      |
|              | H14-CHO: homogenates of   | similar isotope effect   |
|              | the rat nasal mucosa      | was observed in the      |
|              | incubated with 3H and14C  | absence of GSH,          |
|              | formaldehyde at total     | presumably due to the    |
|              | formaldehyde              | oxidation of 3HCHO and   |
|              | concentrations ranging    | H14CHO, which can bind   |
|              | from 0.1 to 11 uM, NAD+   | to DNA resulting in an   |
|              | (1 mM), GSH (15 mM), and  | isotope ratio higher     |
|              | pyrazole (1mM)            | 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)  | **NOAEL: 2.5 mg/m^3^**   |
|              | Responses of the Nasal    |                          |
|              | Mucociliary Apparatus of  | **LOAEL: 7.4 mg/m^3^**   |
|              | F-344 Rats to             |                          |
|              | Formaldehyde Gas.         | Rats exposed to 2.5,     |
|              | Toxicology and Applied    | 7.4, or 19 mg/m^3^       |
|              | Pharmacology 82: 1-13.    | exhibited                |
|              |                           | concentration-related    |
|              | **Open Literature**       | evidence of eye and nose |
|              |                           | irritation, including    |
|              | Rat                       | ocular and nasal         |
|              |                           | discharge, and reddish   |
|              | 0, 0.7, 2, 6, or 15 ppm   | exudate in the nasal     |
|              | (0, 0.62, 2.5, 7.4, or 19 | passages.                |
|              | mg/m^3^) 6 hour exposures |                          |
|              | for up to 3 week duration | 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/m^3^ 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/m^3^, the effects     |
|              |                           | were much less extensive |
|              |                           | and they were minimal or |
|              |                           | absent at 2.5 mg/m^3^.   |
|              |                           | Localized inhibition of  |
|              |                           | ciliary activity on the  |
|              |                           | ventral margin of the    |
|              |                           | nasoturbinate was        |
|              |                           | observed in a few        |
|              |                           | animals exposed to 2.5   |
|              |                           | mg/m^3^ 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/m^3^, and   |
|              |                           | more posterior regions   |
|              |                           | were affected after 9    |
|              |                           | days. In rats exposed to |
|              |                           | 7.4 mg/m^3^              |
|              |                           | formaldehyde, no         |
|              |                           | consistent effects on    |
|              |                           | the mucus flow rate were |
|              |                           | observed except in areas |
|              |                           | exhibiting mucostasis.   |
|              |                           | At 2.5 mg/m^3^, there    |
|              |                           | was no evidence of       |
|              |                           | reduced mucus flow rate. |
|              |                           |                          |
|              |                           | In rats exposed to 19    |
|              |                           | mg/m^3^ 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/m^3^ 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/m^3^, 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/m^3^.  |
|              |                           | 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/m^3^.             |
+--------------+---------------------------+--------------------------+
| Inhalation   | Monticello, et al. (1991) | **NOAEL: 2.5 mg/m^3^**   |
| Short and    | Regional Increases in Rat |                          |
| Intermediate | Nasal Epithelial Cell     | **LOAEL: 7.4 mg/m^3^**   |
| term         | Proliferation following   |                          |
|              | Acute and Subchronic      | Animals exposed to 2.5   |
|              | Inhalation of             | mg/m^3^ or less had no   |
|              | Formaldehyde. Toxicology  | microscopic evidence of  |
|              | and Applied Pharmacology  | formaldehyde-induced     |
|              | 111: 409-421.             | lesions.                 |
|              |                           | Formaldehyde-induced     |
|              | **Open Literature**       | lesions at higher doses  |
|              |                           | were confined to nasal   |
|              | Rats (36/group)           | passages primarily       |
|              |                           | involving the            |
|              | 0, 0.7, 2, 6, 10, or 15   | cuboidal-transitional    |
|              | ppm (0, 0.87, 2.5, 7.4,   | and respiratory          |
|              | 12, or 19 mg/m^3^), 6     | epithelium. Light        |
|              | hr/day for 1, 4, or 9     | microscopic lesions were |
|              | days, or 6 weeks (5       | not observed in the      |
|              | days/week)                | 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/m^3^         |
|              |                           | 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/m^3^)       |
|              |                           | 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/m^3^  |
|              |                           | 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/m^3^    |
|              |                           | 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/m^3^, 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/m^3^ 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/m^3^  |
|              |                           | 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/m^3^ 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/m^3^ 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/m^3^,  |
|              |                           | was not apparent at      |
|              |                           | these higher             |
|              |                           | concentrations.          |
+--------------+---------------------------+--------------------------+
| Other --     | Kane, Laurel E.; and      | **RD~50~: 3.84 mg/m^3^** |
| Sensory      | Alarie, Yves. (1977)      |                          |
| Irritation   | Sensory Irritation to     |                          |
|              | Formaldehyde and Acrolein |                          |
| Purity: 37%  | 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.               |                          |
+--------------+---------------------------+--------------------------+
| Other -      | Steinhagen, WH; Barrow,   | **RD50: 3.2 ppm          |
| Sensory      | CS. (1984) Sensory        | (2.1--4.7 ppm) (Swiss    |
| Irritation   | irritation                | Webster)**               |
|              | structure-activity study  |                          |
|              | of inhaled aldehydes in   | **RD50: 4.90 ppm         |
|              | B6C3F1 and Swiss-Webster  | (3.9--6.4 ppm)           |
|              | mice. Toxicol Appl        | (B6C3F1)**               |
|              | Pharmacol 72:495-503.     |                          |
|              |                           | The difference in        |
|              | **Open Literature**       | results between strains  |
|              |                           | was not statistically    |
|              | M Swiss Webster and       | significant. On the      |
|              | B6C3F1 mice (3-4/dose)    | average, α, β            |
|              |                           | unsaturated aliphatic    |
|              | 10 minute head-only       | aldehydes and            |
|              | exposure to formaldehyde  | formaldehyde were        |
|              | and other aldehydes       | 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     | Gardner, RJ; Burgess, BA; | **RD50: 13.8 ppm**       |
|              | Kennedy, GL, Jr. (1985)   |                          |
| Other -      | Sensory irritation        | Estimate was about       |
| Sensory      | potential of selected     | threefold less than the  |
| Irritation   | nasal tumorigens in the   | 31.7 ppm reported for    |
|              | rat. Food Chem Toxicol    | male F344 rats (Barrow   |
| Purity: 5%   | 23:87-92.                 | et al., 1983). This may  |
|              |                           | indicate differences in  |
|              | []{.mark}                 | responsiveness to        |
|              |                           | formaldehyde among       |
|              | **Open Literature**       | different strains of     |
|              |                           | rat. Concentrations of   |
|              | 8-week-old Crl-CD male    | 5.5 ppm or more produced |
|              | rats (4/group)            | considerable depression  |
|              |                           | in respiratory rate. The |
|              | []{.mark}                 | decrease was observed    |
|              |                           | during the first minute  |
|              | The RD50 of eight         | of exposure and achieved |
|              | chemicals was determined  | a maximum at about 3     |
|              | to determine whether      | minutes. Some recovery   |
|              | there was a correlation   | was observed during      |
|              | between the ability of a  | exposure from 3 to 10    |
|              | chemical to produce       | minutes after the start  |
|              | sensory irritation and    | but was incomplete       |
|              | tumorigenic potency.      | during the first 5       |
|              | Groups of rats were       | minutes after exposure.  |
|              | exposed for 15 minutes to | Taking the results of    |
|              | various concentrations of | the eight chemicals      |
|              | formaldehyde ranging from | together, sensory        |
|              | 0.77 to 24.9 ppm after a  | irritation potency did   |
|              | 5-minute pretest exposure | not correlate with the   |
|              | to control air.           | carcinogenic potency     |
|              |                           | indicated by long-term   |
|              | []{.mark}                 | inhalation experiments.  |
+--------------+---------------------------+--------------------------+
| 870.1300     | Chang, JC; Barrow, CS.    | Exposure to formaldehyde |
|              | (1984) Sensory irritation | at 15 ppm for 6          |
| Other -      | tolerance and             | hours/day, 5 days/week   |
| Sensory      | cross-tolerance in F-344  | failed to induce         |
| Irritation   | rats exposed to chlorine  | tolerance. However,      |
|              | or formaldehyde gas.      | tolerance was observed   |
| Purity: 95%  | Toxicol Appl Pharmacol    | following exposure to 28 |
| para         | 76:319-327.               | ppm formaldehyde for 4   |
| formaldehyde |                           | days. The                |
|              | []{.mark}                 | concentration-response   |
|              |                           | curve in these animals   |
|              | **Open Literature**       | was significantly        |
|              |                           | different than that of   |
|              | []{.mark}                 | naïve animals, with an   |
|              |                           | increase in RD50         |
|              | M Fischer 344 (CDF\[F     | estimate for this        |
|              | 344\]Crl/Br) rats         | exposure duration from   |
|              | (4/group)                 | 31.7 to 70.2 ppm.        |
|              |                           |                          |
|              | []{.mark}                 |                          |
|              |                           |                          |
|              | 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.    |                          |
+--------------+---------------------------+--------------------------+
| 870.1300     | Cassee, FR; Arts, JH;     | **RD50: 10.0 (95% CI     |
|              | Groten, JP; et al. (1996) | 4.7--13.7)**             |
| Other -      | Sensory irritation to     |                          |
| Sensory      | mixtures of formaldehyde, |                          |
| Irritation   | acrolein, and             |                          |
|              | acetaldehyde in rats.     |                          |
| Purity:      | Arch Toxicol 70:329-337.  |                          |
| 90%-92%      |                           |                          |
| Para         | **Open Literature**       |                          |
| formaldehyde |                           |                          |
|              | 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.                 |                          |
+--------------+---------------------------+--------------------------+
| 870.1300     | Kulle, TJ; Cooper, GP.    | **The mean thresholds    |
|              | (1975) Effects of         | were 0.25 ppm for        |
| Other -      | formaldehyde and ozone on | formaldehyde**, 5.0 ppm  |
| Sensory      | the trigeminal nasal      | for ozone, and 0.30 ppm  |
| Irritation   | sensory system. Arch      | for amyl alcohol.        |
|              | Environ Health            |                          |
| Purity: 95%  | 30:237-243.               | There was a progressive  |
| Para         |                           | depression in response   |
| formaldehyde | **Open Literature**       | to amyl alcohol with     |
|              |                           | increasing stimulus of   |
|              | Adult M Sprague-Dawley    | formaldehyde             |
|              | rats (5/experiment)       | concentration \[p \<     |
|              |                           | 0.01, analysis of        |
|              | []{.mark}                 | variance (ANOVA)\]. The  |
|              |                           | effects of exposure to   |
|              | The effects of            | 2.0 ppm were similar     |
|              | formaldehyde on           | regardless of whether it |
|              | trigeminal nerve afferent | was presented            |
|              | activity in rats was      | immediately as a         |
|              | investigated. Electrodes  | separate exposure or as  |
|              | were implanted through a  | the final concentration  |
|              | dissection in the right   | of a progressively       |
|              | eye orbit. The authors    | increasing series. The   |
|              | state that because the    | response to amyl alcohol |
|              | ethmoid nerve and         | did not fully recover    |
|              | trigeminal nerve          | within the 1-hour        |
|              | responded similarly the   | extended recovery        |
|              | experiments were          | period. Thus it appeared |
|              | performed with the        | that the afferent        |
|              | nasopalatine nerve to     | function depression was  |
|              | eliminate potential       | not due to receptor      |
|              | contribution from the     | adaptation or            |
|              | mechanoreceptor fibers in | insufficient time for    |
|              | the ethmoid nerve. The    | formaldehyde diffusion   |
|              | sensory threshold was     | away from receptor       |
|              | determined by             | sites.                   |
|              | 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.                  |                          |
+--------------+---------------------------+--------------------------+
| 870.1300     | Tsubone, H; Kawata, M.    | The vapor concentration  |
|              | (1991) Stimulation to the | associated with a 50%    |
| Other -      | trigeminal afferent nerve | increase in nerve        |
| Sensory      | of the nose by            | activity over the level  |
| Irritation   | formaldehyde, acrolein,   | of control gas was       |
|              | and acetaldehyde gases.   | calculated as            |
|              | Inhal Toxicol 3:211-222.  | approximately 1.8 ppm    |
|              |                           | for formaldehyde.        |
|              | **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.           |                          |
+--------------+---------------------------+--------------------------+
| Sensory      | **MRID No. 43170601**     | No treatment related     |
| Irritation   |                           | mortality was observed.  |
|              | Werley et al. (1994).     | Mice exposed to          |
| F            | Glutardehyde and          | formaldehyde showed no   |
| ormaldehyde, | Formaldehyde: Sensory     | treatment-related        |
| Lot No.      | Irritation Study in       | clinical findings. All   |
| 420807, 10   | Swiss-Webster Mice. Union | mice exposed to          |
| %a.i.        | Carbide Lab Project No.   | formaldehyde at          |
| (methanol    | 91U0123.                  | 99.1mg/m3 showed         |
| free)        |                           | increased lacrimation    |
|              | **a                       | and periocular wetness.  |
|              | cceptable/non-guideline** | Slight reductions in     |
|              |                           | body weight were         |
|              | Male Swiss-Webster ND4    | observed in some of the  |
|              | mice (40-55 days old at   | mice at the highest      |
|              | start of study), 4        | exposure doses for       |
|              | animals/dose              | formaldehyde.            |
|              |                           |                          |
|              | 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/m^3^), 30 min,         |                          |
|              | head-only chambers        |                          |
+--------------+---------------------------+--------------------------+
| Immunologic  | Tarkowski, M. and Gorski, | Following sensitization, |
| S            | P. 1995. Increased IgE    | titer of serum           |
| ensitization | antiovalbumin level in    | anti-ovalbumin IgE       |
|              | mice exposed to           | antibodies were          |
|              | formaldehyde. Int. Arch.  | significantly higher in  |
|              | Allergy Immunol. 106:     | mice exposed to          |
|              | 422--424.                 | formaldehyde 6 hours/day |
|              |                           | for 10 days, compared to |
|              | **Open Literature**       | mice exposed 6           |
|              |                           | hours/week for 7 weeks   |
|              | F Balb/c Mouse            | or untreated. The        |
|              |                           | authors concluded that   |
|              | Groups were exposed to 2  | formaldehyde facilitates |
|              | mg/m^3^ formaldehyde      | animal sensitization to  |
|              | either 6 hours/day for 10 | ovalbumin through        |
|              | days, or to 6 hours/day   | histological changes     |
|              | once a week for 7 weeks.  | occurring in the upper   |
|              | Then all mice were        | respiratory tract.       |
|              | sensitized intranasally   |                          |
|              | with ovalbumin.           |                          |
+--------------+---------------------------+--------------------------+
| Immunologic  | Riedel, F., et al. C.H.L. | Following ovalbumin      |
| S            | 1996. Formaldehyde        | challenge, 10/12 animals |
| ensitization | Exposure Enhances         | exposed to 310 ug/m^3^   |
|              | Sensitization in the      | showed bronchial         |
|              | Guinea Pig. Allergy 51:   | obstruction, compared    |
|              | 94--99.                   | with 3/12 control        |
|              |                           | animals (p\<0.01);       |
|              | **Open Literature**       | animals exposed to 160   |
|              |                           | ug/m^3^ were not         |
|              | Guinea Pig (12/group)     | significantly different  |
|              |                           | from controls.           |
|              | Animals were exposed to   | Anti-ovalbumin IgG       |
|              | formaldehyde              | antibodies were not      |
|              | concentrations of 0       | detectable (\<10 ELISA   |
|              | (controls), 160 or 310    | units or EU) in any      |
|              | ug/m^3^ (0.13 and 0.25    | animal at day 0, but     |
|              | ppm) for 5 days, followed | were detectable in 0/12  |
|              | by sensitization to       | controls, 3/12 animals   |
|              | inhaled ovalbumin at days | exposed to 160 ug/m^3^,  |
|              | 5 and 19. On day 26, a    | and 6/12 animals exposed |
|              | bronchial provocation     | to 310 ug/m^3^ at day    |
|              | test with ovalbumin was   | 25.                      |
|              | 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.               |                          |
+--------------+---------------------------+--------------------------+
| I            | Jakab, GJ. (1992)         | Mice exposed to 15 ppm   |
| mmunological | Relationship between      | formaldehyde for the 4   |
|              | carbon black              | hours following          |
|              | particulate-bound         | bacterial infection      |
|              | formaldehyde, pulmonary   | (Regimen A) had          |
|              | antibacterial defenses,   | approximately an 8%      |
|              | and alveolar macrophage   | increase in bacteria,    |
|              | phagocytosis. Inhal       | indicating decreased     |
|              | Toxicol 4:325-342.        | host resistance          |
|              |                           | (p=0.006). Pre-infection |
|              | **Open Literature**       | exposure to 0.5 or 1.0   |
|              |                           | ppm did not change       |
|              | White Female Swiss Mouse  | bacterial loading 4      |
|              |                           | hours after infection    |
|              | Mice were exposed to      | (Regimen B). However,    |
|              | formaldehyde after        | combining an 18-hour     |
|              | bacterial infection       | pre-infection            |
|              | (Regimens A and C),       | formaldehyde exposure    |
|              | before bacterial          | with a 4-hour            |
|              | infection (Regimen B), or | post-infection 1 ppm     |
|              | before and after          | formaldehyde exposure    |
|              | infection (Regimen D). In | increased pulmonary      |
|              | the first trial mice were | bacterial loading by     |
|              | exposed to 0, 1.0, 5.0,   | approximately 6.5%       |
|              | 10.0, or 15.0 ppm         | (p\<0.05). Increased     |
|              | formaldehyde (0, 1.2,     | bacterial loading        |
|              | 6.2, 12.3, or 18.5        | indicates that           |
|              | mg/m^3^). The remaining   | formaldehyde exposure    |
|              | mice were exposed to 0,   | (Regimens A and D)       |
|              | 0.5, or 1.0 ppm           | reduced pulmonary        |
|              | formaldehyde (0, 6.2, or  | bacterial resistance.    |
|              | 1.2 mg/m^3^). A 30-minute | This is in apparent      |
|              | exposure to an infectious | contradiction to the     |
|              | aerosol of S. aureus      | findings of increased    |
|              | deposited 2x105           | host resistance by Dean  |
|              | staphylococci in the      | et al. (1984). However,  |
|              | lungs. Bacterial loading  | there are important      |
|              | was determined in         | differences between the  |
|              | homogenized lung tissue   | studies. The studies by  |
|              | by culturing diluted      | Jakab (1992) are acute   |
|              | aliquots for an estimate  | studies examining        |
|              | of bacteria present       | effects at the           |
|              | immediately after loading | respiratory tract where  |
|              | and 4 hours later.        | 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) | Exposure of mice to 19   |
|              | The Effect of             | mg/m^3^, 6 hr/day, 5     |
|              | Formaldehyde Exposure     | days/week for 3 weeks    |
|              | upon the Mononuclear      | did not appreciably      |
|              | Phagocyte System of Mice. | alter the number of      |
|              | Toxicology and Applied    | resident macrophages in  |
|              | Pharmacology 88: 165-174. | the peritoneal cavit+y   |
|              |                           | or that elicited in      |
|              | **Open Literature**       | response to MVE-2.       |
|              |                           |                          |
|              | Female Mouse              |                          |
|              |                           |                          |
|              | 15 ppm (19 mg/m^3^), 6    |                          |
|              | hr/day, 5 days/week. 3    |                          |
|              | weeks                     |                          |
+--------------+---------------------------+--------------------------+
| Dermal       | Bartnik, F.G., Gloxhuber  | Under non --occlusive    |
| absorption   | Chr., and Zimmermann V.   | conditions, absorption   |
|              | (1985) Percutaneous       | of radiolabeled          |
|              | Absorption of             | formaldehyde in the      |
|              | Formaldehyde in Rats.     | cosmetic cream           |
|              | Toxicology Letters. v.    | preparation was          |
|              | 25. p. 167 - 172.         | published as 6.1% in     |
|              |                           | males and 9.2% in        |
|              | **Open Literature**       | females. Occlusive       |
|              |                           | conditions reported      |
|              | 10 Male/4 Female Rat      | absorption as 3.4% in    |
|              |                           | males.                   |
|              | \[14C\] 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              |                          |
+--------------+---------------------------+--------------------------+
| Other        | Hester, et al. (2003)     | Siginificance analysis   |
|              | Formaldehyde-Induced Gene | of microarrays (SAM)     |
| Purity: Not  | Expression in F344 Rat    | hybridization data       |
| Reported     | Nasal Respiratory         | revealed that 24 of the  |
|              | Epithelium. Toxicology    | 1185 genes queried were  |
|              | 187: 13-24.               | significantly            |
|              |                           | up-regulated and 22      |
|              | **Open Literature**       | genes were significantly |
|              |                           | downregulated. The       |
|              | 8 F344 Male Rats          | identified genes with    |
|              |                           | FA-induced change in     |
|              | 40 ul aliquots of water   | expression belong to the |
|              | or formaldehyde (400 mM)  | functional gene          |
|              | were instillled into      | categories xenobiotic    |
|              | nostrils using a pipette. | metabolism, cell cycle,  |
|              | Twenty-four hours after   | apoptosis, and DNA       |
|              | treatment, nasal          | repair. These data       |
|              | epithelium was recovered  | suggest that multiple    |
|              | from which total RNA was  | pathways are             |
|              | used to generate cDNA     | dysregulated by          |
|              | probes.                   | formaldehyde exposure,   |
|              |                           | including those involved |
|              |                           | in DNA synthesis/repair  |
|              |                           | and regulation of cell   |
|              |                           | proliferation.           |
+--------------+---------------------------+--------------------------+
| 870.3100     | Vargova M, Wagnerova J,   | **NOAEL: 40 mg/kg/day**  |
|              | Liskova A, et al. (1993)  |                          |
| Other        | Subacute immunotoxicity   | **LOAEL: 80 mg/kg/day**  |
|              | study of formaldehyde in  | for an increase in the   |
| Purity:      | male rats. Drug Chem      | incidence of             |
| 28.44%       | Toxicol 16:255-275.       | hepatocelluar            |
|              |                           | vacuolization            |
|              | **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       |                          |
+--------------+---------------------------+--------------------------+
| 870.3465     | Casanova, Mercedes, et    | **NOAEL: 2.5 mg/m^3^**   |
|              | al. (1994) DNA-Protein    |                          |
| Other        | Cross-links and Cell      | **LOAEL: 7.4 mg/m^3^**   |
|              | Replication at Specific   |                          |
| Purity: 14-C | Sites in the Nose of F344 | Visible lesions were     |
| Para         | Rats Exposed              | only observed in animals |
| formaldehyde | Subchronically to         | exposed to 18.6 mg/m^3^  |
| (97.3-99%),  | Formaldehyde. Fundamental | for 12 weeks. No         |
|              | and Applied Toxicology    | formaldehyde-induced     |
| Unlabeled    | 23: 525-536.              | lesions were observed in |
| para         |                           | the squamous and         |
| formaldehyde | **Open Literature**       | olfactory regions of the |
| (95%)        |                           | nose. Rats exposed to    |
|              | Rats inhalation (20       | 0.87 or 2.5 mg/m^3^ were |
|              | rats/group, 10 of which   | indistinguishable from   |
|              | are preexposed (PE), 10   | controls. At 7.4         |
|              | not (N))                  | mg/m^3^, lesions were    |
|              |                           | confined to multifocal   |
|              | 0.7, 2, 6, 10, or 15 ppm  | epithelial hypertrophy,  |
|              | (0, 0.87, 2.5, 7.4, 12.4, | hyperplasia, and         |
|              | or 18.6 mg/m^3^)          | squamous metaplasia of   |
|              | Preexposed animals        | the lM, while the rest   |
|              | whole-body exposed 6      | of the nose was          |
|              | hr/day, 11 weeks +4 days) | unaffected. At 12.39     |
|              | On the 5th day of the     | mg/m^3^, the most        |
|              | 12th week, animals        | characteristic response  |
|              | exposed once nose-only    | was squamous metaplasia  |
|              | for 3 hours H14-CHO using | of the transitional      |
|              | nominal concentrations    | epithelial lining of the |
|              | DPX estimation: 6 ppm or  | LM and medial            |
|              | 10 ppm (7.4 or 12.4       | maxilloturbinate, and    |
|              | mg/m^3^) On 5th day of    | mild epithelial          |
|              | 12th week, exposed to     | hyperplasia of the       |
|              | unlabeled formaldehyde    | midseptum with generally |
|              | once nose-only for 3      | mild inflammatory cell   |
|              | hours using nominal       | infiltration.            |
|              | concentration             |                          |
|              |                           | At 18.6 mg/m^3^,         |
|              |                           | 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/m^3^  |
|              |                           | 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/m^3^,        |
|              |                           | 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/m^3^.    |
+--------------+---------------------------+--------------------------+

**APPENDIX C - Mutagenicity Profile for Formaldehyde and
Paraformaldehyde**

+-------------+--------------------+--------------+------------------+
| **Table C1. |                    |              |                  |
| M           |                    |              |                  |
| utagenicity |                    |              |                  |
| data for    |                    |              |                  |
| For         |                    |              |                  |
| maldehyde** |                    |              |                  |
+=============+====================+==============+==================+
| **Guideline | **MRID No./**      | **Dosing and | **Results**      |
| No./**      |                    | Animal       |                  |
|             | **Reference        | I            |                  |
| **Study     | Information/**     | nformation** |                  |
| Type**      |                    |              |                  |
|             | **Study            |              |                  |
|             | Classification**   |              |                  |
+-------------+--------------------+--------------+------------------+
| **Mut       |                    |              |                  |
| agenicity** |                    |              |                  |
+-------------+--------------------+--------------+------------------+
| 870.5100    | **MRID 00132156**  | 0.001, 0.01, | **Negative**     |
|             |                    | 0.10, 1.0,   |                  |
| Bacterial   | Jagannath, D.      | or 5.0 µL.   |                  |
| reverse     | (1978)             |              |                  |
| mutation    | Mutagenicity       | Salmonella   |                  |
| test        | Evaluation of      | tester       |                  |
|             | Dantoin DMDMH-55   | strains      |                  |
|             | 40-697 737543 in   | TA-98,       |                  |
|             | the Ames           |              |                  |
|             | Sa                 | TA-100,      |                  |
|             | lmonella/Microsome | TA-1535      |                  |
|             | Plate Test: LBI    |              |                  |
|             | Project No. 20838. | TA-I 537 and |                  |
|             | Final rept.        | TA-1538.     |                  |
|             | (Unpublished study | S            |                  |
|             | received May 9,    | accharamyces |                  |
|             | 1983 under         | indicator    |                  |
|             | 38906-5; prepared  | organisms,   |                  |
|             | by Litton          | strain 04.   |                  |
|             | Bionetics, Inc.,   |              |                  |
|             | sub- mitted by     |              |                  |
|             | Glyco, Inc.,       |              |                  |
|             | Greenwich, CT;     |              |                  |
|             | CDL:250313-A)      |              |                  |
|             |                    |              |                  |
|             | **Supplementary**  |              |                  |
+-------------+--------------------+--------------+------------------+
| 870.5100    | **MRID 00132157**  | Test         | **Positive**     |
|             |                    | material     |                  |
| Bacterial   | Haworth, S.;       | (447:34-3,   | Test article     |
| reverse     | Lawlor, T.; Burke, | MA #T1804)   | caused did cause |
| mutation    | P.; et al. (1982). | tested at    | a positive       |
| test        | Salmonella/        | co           | response         |
|             |                    | ncentrations | (3.2-fold        |
|             | M                  | of 3.0,      | increase) on     |
|             | ammalian-microsome | 15.0, 75.0,  | tester strain    |
|             | Preincubation      | 150, or 300  | TA98 without     |
|             | Mutagenicity Assay | µg/plate.    | metabolic        |
|             | (Ames Test): Test  |              | activation. A    |
|             | Article 447:34-3:  | Tester       | 1.9-fold         |
|             | Study No.          | strains      | increase was     |
|             | T1804.502.         | TA98, TA100, | observed on TA98 |
|             | (Unpublished study | TA1535,      | with metabolic   |
|             | received May 9,    | TA1357,      | activation.      |
|             | 1983 under         | TA1358 ±     | Also, increases  |
|             | 38906-5; prepared  | metabolic    | of 2.2-fold and  |
|             | by Microbiological | activation   | 1.7-fold were    |
|             | Assoc., submitted  | with araclor | observed on      |
|             | by Glyco, Inc.,    | induced rat  | tester strain    |
|             | Greenwich, CT;     | liver        | TA100 with and   |
|             | CDL:250313-B).     | microsomes.  | without          |
|             |                    |              | activation,      |
|             | **Acceptable**     |              | respectively.    |
+-------------+--------------------+--------------+------------------+
| 870.5100    | O\'DONOVAN, MR AND | 0-200        | Pre-incubation   |
|             | MEE,CD;            | ug/plate,    | exposure:        |
| Bacterial   | FORMALDEHYDE IS A  | pr           | positive for     |
| reverse     | BACTERIAL MUTAGEN  | e-incubation | mutagenicity in  |
| mutation    | IN A RANGE OF      | exposure and | TA98, TA100, and |
| test        | SALMONELLA AND     | standard     | TA102 and both   |
|             | ESCHERICHIA        | plate-       | E.coli strains.  |
|             | INDICATOR STRAINS; | i            |                  |
|             | MUTAGENESIS        | ncorporation | Standard         |
|             | 8(6):577-581, 1993 | assays       | pla              |
|             |                    |              | te-incorporation |
|             | **Open             | S.           | assays:          |
|             | Literature**       | typhimurium  |                  |
|             |                    | Strains      | Consistent       |
|             |                    | TA1535,      | mutagenicity was |
|             |                    | TA1537,      | seen only for    |
|             |                    | TA1538,      | TA100 and        |
|             |                    | TA98, TA100, | WP2uvrA          |
|             |                    | and TA102    | (pKM101).        |
|             |                    | and E.coli   |                  |
|             |                    | Strains      | No evidence of   |
|             |                    | WP2(pKM101)  | mutagenicity was |
|             |                    | and WP2uvrA  | seen for TA1535, |
|             |                    | (pKM101)     | TA1537, or       |
|             |                    |              | TA1538 using     |
|             |                    | Purity: 37%  | either method of |
|             |                    |              | exposure.        |
+-------------+--------------------+--------------+------------------+
| 870.5100    | Schmid, E., W.     | The tests    | Plate Assay:     |
|             | Goggelmann; and M. | were carried | weak positive    |
| Bacterial   | Bauchinger. (1986) | out using    | response         |
| reverse     | Fo                 | the plate    |                  |
| mutation    | rmaldehyde-induced | i            | Pre-Incubation   |
| test        | Cytotoxic,         | ncorporation | Method: Without  |
|             | Genotoxic, and     | assay and    | S9 mix,          |
|             | Mutagenic Response | the          | a1.6-fold        |
|             | in Human           | pr           | increase of      |
|             | Lymphocytes and    | e-incubation | revertant        |
|             | Salmonella         | method +/-   | numbers over     |
|             | typhimurium.       | S9           | controls was     |
|             | Mutagenesis vol. 1 | activation   | induced. With S9 |
|             | no. 6 p. 427-431.  | at doses of  | mix, a 2.7-fold  |
|             |                    | 0-1.5mM and  | increase of      |
|             | **Open             | 0-0.3mM      | revertant        |
|             | Literature**       | f            | numbers over     |
|             |                    | ormaldehyde, | controls was     |
|             |                    | r            | induced.         |
|             |                    | espectively. |                  |
|             |                    |              |                  |
|             |                    | The          |                  |
|             |                    | incubation   |                  |
|             |                    | mixture      |                  |
|             |                    | consisted of |                  |
|             |                    | 0.5 ml       |                  |
|             |                    | phosphate    |                  |
|             |                    | buffer or S9 |                  |
|             |                    | mix and10 ul |                  |
|             |                    | of an        |                  |
|             |                    | appropriate  |                  |
|             |                    | c            |                  |
|             |                    | oncentration |                  |
|             |                    | of           |                  |
|             |                    | formaldehyde |                  |
|             |                    | in water.    |                  |
|             |                    |              |                  |
|             |                    | S.           |                  |
|             |                    | typhimurium  |                  |
|             |                    | Strain TA100 |                  |
|             |                    | (0.1 ml      |                  |
|             |                    | bacterial    |                  |
|             |                    | suspension   |                  |
|             |                    | of about     |                  |
|             |                    | 10\*8 cells  |                  |
|             |                    | were used in |                  |
|             |                    | the          |                  |
|             |                    | pr           |                  |
|             |                    | e-incubation |                  |
|             |                    | method)      |                  |
|             |                    |              |                  |
|             |                    | Purity: 37%  |                  |
+-------------+--------------------+--------------+------------------+
| 870.5100    | Temcharoen, P;     | The capacity | Both toxicity    |
|             | Thilly, WG. (1983) | of           | and mutagenicity |
| Bacterial   | Toxic and          | formaldehyde | were obtained at |
| reverse     | mutagenic effects  | to induce    | formaldehyde     |
| mutation    | of formaldehyde in | forward      | concentrations   |
| test        | Salmonella         | mutations to | of 0.17 mM in    |
|             | typhimurium. Mutat | 8-azaguanine | the absence of   |
|             | Res 119:89-93.     | resistance   | S9 and 0.33 mM   |
|             |                    | in was       | in the presence  |
|             | **Open             | examined.    | of S9. The       |
|             | Literature**       | Formaldehyde | authors noted    |
|             |                    | co           | that, while the  |
|             |                    | ncentrations | S9 might be      |
|             |                    | of 0.17 mM   | enzyme           |
|             |                    | in the       | inactivating     |
|             |                    | absence of   | formaldehyde,    |
|             |                    | S9 and 0.33  | the binding of   |
|             |                    | mM in the    | formaldehyde to  |
|             |                    | presence of  | amino groups of  |
|             |                    | S9.          | proteins in the  |
|             |                    |              | S9 would         |
|             |                    | S.           | effectively      |
|             |                    | typhimurium  | reduce the       |
|             |                    | TM 677, a    | concentration of |
|             |                    | his^+^       | formaldehyde     |
|             |                    | revertant of | entering the     |
|             |                    | TA 1535      | cells.           |
|             |                    |              |                  |
|             |                    | Purity: 37%  |                  |
+-------------+--------------------+--------------+------------------+
| 870.5200    | Mouse Lymphoma     | Doses of 0,  | An increase in   |
|             | L5178Y Cell TK     | 0.1, 0.5, 1, | mutation         |
| Mouse       | Locus Assay for    | 5, 10 or20   | frequency was    |
| visible     | Mutagenicity; A    | ug/ml        | reported,        |
| specific    | Study with         | without      | especially at 10 |
| locus test  | Formaldehyde.      | activation   | and 20 ug/ml.    |
|             | (DuPont, 7/28/80,  | only, four   |                  |
|             | Haskell Laboratory | trials       |                  |
|             | Report No.         |              |                  |
|             | 581-80).           | Mouse        |                  |
|             |                    | Lymphoma     |                  |
|             | **Open             | L5178Y Cell  |                  |
|             | Literature**       |              |                  |
|             |                    | Purity: 37%  |                  |
+-------------+--------------------+--------------+------------------+
| 870.5275    | Valencia, R., J.M. | Doses of     | **Positive**     |
|             | Mason, and S.      | 2,600 and    |                  |
| Sex-linked  | Zimmering. (1989)  | 1,100 ppm    |                  |
| recessive   | Chemical           |              |                  |
| lethal test | Mutagenesis        | D.           |                  |
| in          | Testing in         | melanogaster |                  |
| Drosophila  | Drosophila. VI.    | (Canton-S M  |                  |
| m           | Interlaboratory    | and Basc F)  |                  |
| elanogaster | Comparison of      |              |                  |
|             | Mutagenicity Tests | Purity: 37%  |                  |
|             | After Treatment of |              |                  |
|             | Larvae.            |              |                  |
|             | Environmental and  |              |                  |
|             | Molecular          |              |                  |
|             | Mutagenesis, v.    |              |                  |
|             | 14, p. 238-244.    |              |                  |
|             |                    |              |                  |
|             | **Open             |              |                  |
|             | Literature**       |              |                  |
+-------------+--------------------+--------------+------------------+
| 870.5375    | **MRID 00132168**  | Test         | **Positive**     |
|             |                    | material     |                  |
| In vitro    | Thilagar, A.;      | (447:34-1)   | Test article     |
| mammalian   | Kumaroo, P.; Pant, | was tested   | caused a         |
| chromosome  | K. (1982)          | at           | significant      |
| aberration  | Cytogenicity       | co           | dose-dependant   |
| test        | Study: Chi- nese   | ncentrations | increase in the  |
|             | Hamster Ovary      | of 28.43,    | frequencies of   |
|             | (CHO) Cells in     | 37.91, or    | chromosome       |
|             | vitro: Test        | 50.55 nL/mL. | aberrations in   |
|             | Article 447:34-1:  |              | the Chinese      |
|             | Study No.          | Chinese      | Hamster Ovary    |
|             | T1802.338.         | hamster      | cells, both with |
|             | (Unpublished study | ovary cells  | and without S-9  |
|             | received May 9,    | (cell        | activation.      |
|             | 1983 under         | repository   |                  |
|             | 38906-5; prepared  | number CCL,  |                  |
|             | by Microbiological | 61)          |                  |
|             | Assoc., submitted  |              |                  |
|             | by Glyco, Inc.,    | Purity: 37%  |                  |
|             | Greenwich, CT;     | Formalin     |                  |
|             | CDL:250313-M)      |              |                  |
|             |                    |              |                  |
|             | **Acceptable**     |              |                  |
+-------------+--------------------+--------------+------------------+
| 870.5375    | Natarajan, A.T. et | In Vitro     | **In Vitro:      |
|             | al. (1983)         |              | Positive**       |
| In Vitro    | Evaluation of the  | CHO cells    |                  |
| mammalian   | mutagenicity of    | exposed to   | Frequencies of   |
| chromosome  | formaldehyde in    | 0, 0.003,    | chromosomal      |
| aberration  | mammalian          | 0.006,       | aberrations and  |
| test        | cytogenics assays  | 0.012, or    | SCEs increased   |
|             | in vivo and vitro. | 0.024 uL/mL  | with increasing  |
|             | Mutation Research  | para         | dose. All        |
|             | 122: 355-360.      | formaldehyde | classes of       |
|             |                    |              | aberration, i.e. |
|             | **Open             | In Vivo      | gaps, breaks,    |
|             | Literature**       | Mouse        | and exchanges,   |
|             |                    |              | were induced by  |
|             |                    | 0.4 mL       | formaldehyde.    |
|             |                    | para         | All the          |
|             |                    | formaldehyde | aberrations were |
|             |                    | injected     | chromatid-type,  |
|             |                    | intra        | indicating that  |
|             |                    | peritoneally | formaldehyde     |
|             |                    | to achieve   | acts as an       |
|             |                    | doses of 0,  | S-dependent      |
|             |                    | 6.25, 12.50, | agent. The       |
|             |                    | or 25.00     | addition of      |
|             |                    | mg/kg        | mammalian        |
|             |                    |              | metabolic        |
|             |                    |              | activation       |
|             |                    |              | system reduced   |
|             |                    |              | the frequencies  |
|             |                    |              | of               |
|             |                    |              | form             |
|             |                    |              | aldehyde-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    | Fon                | Mice         | **Negative**     |
|             | tignie-Houbrechts, | received an  |                  |
| Mammalian   | N. (1981) Genetic  | i.p.         | No chromosomal   |
| spe         | Effects of         | injection of | lesions were     |
| rmatogonial | Formaldehyde in    | 50 mg/kg     | revealed         |
| chromosomal | the Mouse.         | formaldehyde |                  |
| aberration  | Mutation Research, |              |                  |
| test        | v. 88, p. 109-114. | M Q Strain   |                  |
|             |                    | Mouse (200   |                  |
|             | **Open             | sp           |                  |
|             | Literature**       | ermatocytes/ |                  |
|             |                    | animal)      |                  |
|             |                    |              |                  |
|             |                    | Purity: 35%  |                  |
+-------------+--------------------+--------------+------------------+
| 870.5450    | Fon                | Mice         | Embryonic death  |
|             | tignie-Houbrechts, | received an  | or pre-post      |
| Rodent      | N. (1981) Genetic  | i.p.         | implantation     |
| dominant    | Effects of         | injection of | death at 1 and 3 |
| lethal      | Formaldehyde in    | 50 mg/kg     | week periods     |
| assay       | the Mouse.         | formaldehyde |                  |
|             | Mutation Research, | and 10 males |                  |
|             | v. 88, p. 109-114. | were caged   |                  |
|             | (as cited in Ma    | with 2       |                  |
|             | and Harris)        | virgin       |                  |
|             |                    | females each |                  |
|             | **Open             | for one      |                  |
|             | Literature**       | week. The    |                  |
|             |                    | females were |                  |
|             |                    | renewed each |                  |
|             |                    | week during  |                  |
|             |                    | 7 weeks.     |                  |
|             |                    |              |                  |
|             |                    | M Q Strain   |                  |
|             |                    | Mouse        |                  |
|             |                    |              |                  |
|             |                    | Purity: 35%  |                  |
+-------------+--------------------+--------------+------------------+
| 870.5450    | Odeigah, P.G.C.    | Five daily   | **Positive**     |
|             | (1997) "Sperm Head | int          |                  |
| Rodent      | Abnormalities and  | erperitonial | The frequency of |
| dominant    | Dominant Lethal    | injections   | dominant lethal  |
| lethal      | Effects of         | of 0.125,    | mutations in     |
| assay       | Formaldehyde in    | 0.250, and   | female rats      |
|             | Albino Rats."      | 0.6 mg/kg    | sired by males   |
|             | Mutation Research  | f            | exposed to       |
|             | 389: 141-148.      | ormaldehyde. | formaldehyde was |
|             |                    | Males were   | significantly    |
|             | **Open             | caged with 2 | higher than the  |
|             | Literature**       | untreated    | control group.   |
|             |                    | 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   |                  |
|             |                    | pos          |                  |
|             |                    | t-injection, |                  |
|             |                    | r            |                  |
|             |                    | espectively. |                  |
|             |                    | 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)    |                  |
+-------------+--------------------+--------------+------------------+
| 870\. 5550  | **MRID 00132169**  | Test         | **Negative**     |
|             |                    | material     |                  |
| Unscheduled | Thilagar, A.;      | (447:34-1)   | The test article |
| DNA         | Pant, K. (1982)    | was tested   | did not cause a  |
| synthesis   | Unscheduled DNA    | at           | significant      |
| in          | Synthesis in Rat   | co           | increase in UDS  |
| mammalian   | Hepatocytes: Test  | ncentrations | in rat           |
| cells in    | Article 447:34-1:  | of 0.0005,   | hepatocytes.     |
| culture     | Study No.          | 0.001,       |                  |
|             | T1802.380002. (Un- | 0.005, 0.01, |                  |
|             | published study    | 0.02, or     |                  |
|             | received May 9,    | 0.04 µL/mL.  |                  |
|             | 1983 under         |              |                  |
|             | 38906-5; prepared  | Primary rat  |                  |
|             | by Microbiological | liver        |                  |
|             | Assoc., submitted  | hepatocytes  |                  |
|             | by Glyco, Inc.,    | --           |                  |
|             | Greenwich, CT;     | Sp           |                  |
|             | CDL:250313-N)      | rague-Dawley |                  |
|             |                    | rats, 2.5 x  |                  |
|             | **Acceptable**     | 10^5^        |                  |
|             |                    | HPC/plate    |                  |
|             |                    |              |                  |
|             |                    | Purity: 37%  |                  |
|             |                    | a.i.         |                  |
+-------------+--------------------+--------------+------------------+
| 870.5900    | A. Basler, W. v.   | The test     | There was a      |
|             | d. Hude, and M.    | compound was | three- to        |
| *In Vitro*  | Scheutwinkel-Reich | added to     | four-fold        |
| Sister      | (1985)             | cell         | increase in the  |
| Chromatid   | "Fo                | cultures 18  | SCE frequency at |
| Exchange    | rmaldehyde-Induced | hours after  | non-toxic doses. |
| Assay       | Sister Chromatid   | seeding 5 x  | However, in the  |
|             | Exchanges in vitro | 10^5^ cells  | presence of an   |
|             | and the Influence  | per 25 cm^2^ | exogenous        |
|             | of the Exogenous   | flask. The   | metabolizing     |
|             | Metabolizing       | exposure     | system, the      |
|             | Systems S9 Mix and | time was 1,  | number of        |
|             | Primary Rat        | 2, 3, or 28  | form             |
|             | Hepatocytes." Arch | hours. In    | aldehyde-induced |
|             | Toxicol 58: 10-13. | the          | SCE's decreased. |
|             |                    | experiments  | S9 mix as well   |
|             | **Open             | with         | as hepatocytes   |
|             | Literature**       | short-term   | reduced the SCE  |
|             |                    | exposure     | frequency to     |
|             | []{.mark}          | (1-3 hours), | nearly that of   |
|             |                    | the medium   | the control      |
|             |                    | was removed  | range. It could  |
|             |                    | after this   | be demonstrated  |
|             |                    | treatment.   | that the         |
|             |                    | The cells    | reduction was    |
|             |                    | were         | not due to an    |
|             |                    | restored in  | unspecific       |
|             |                    | medium       | binding of       |
|             |                    | supplemented | formaldehyde to  |
|             |                    | with         | macromolecules   |
|             |                    | 5-bromo-2-   | of the added S9  |
|             |                    | deoxyuridine | mix. The         |
|             |                    | (BrdU). The  | decrease in      |
|             |                    | cells were   | genotoxic        |
|             |                    | cultured in  | effects, due to  |
|             |                    | the presence | rapid            |
|             |                    | of BrdU      | metabolisation   |
|             |                    | (10^-5^ M)   | of formaldehyde  |
|             |                    | for 28 h,    | in vitro and un  |
|             |                    | with         | vivo, explains   |
|             |                    | colcemide    | the differences  |
|             |                    | (0.1 µg/ml)  | between results  |
|             |                    | for the last | obtained in the  |
|             |                    | 4 h. In the  | in vitro         |
|             |                    | experiments  | experiments --   |
|             |                    | with         | performed        |
|             |                    | long-term    | without          |
|             |                    | exposure,    | metabolizing     |
|             |                    | the cells    | systems -- and   |
|             |                    | were         | in vivo results. |
|             |                    | 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 cm^2^     |                  |
|             |                    | 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, |                  |
|             |                    | 10^6^ viable |                  |
|             |                    | hepatocytes  |                  |
|             |                    | were added   |                  |
|             |                    | to the       |                  |
|             |                    | monolayer.   |                  |
|             |                    | After 2 hr,  |                  |
|             |                    | the          |                  |
|             |                    | nonattached  |                  |
|             |                    | hepatocytes  |                  |
|             |                    | were sucked  |                  |
|             |                    | off and the  |                  |
|             |                    | different    |                  |
|             |                    | co           |                  |
|             |                    | ncentrations |                  |
|             |                    | 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        |                  |
|             |                    |              |                  |
|             |                    | Purity: 37%  |                  |
|             |                    | Form         |                  |
|             |                    | aldehyde/10% |                  |
|             |                    | Methanol     |                  |
+-------------+--------------------+--------------+------------------+
| 870.5915    | Kligerman,AD;      | Rats were    | There were no    |
|             | Phelps, MC;        | exposed to   | increases in     |
| In Vivo     | Erexson, GL.       | 0.5, 6, or   | either SCE or    |
| Sister      | (1984) Cytogenetic | 15 ppm (0.6, | chromosome       |
| Chromatid   | analysis of        | 7.4, 18.5    | aberrations at   |
| Exchange    | lymphocytes from   | mg/m^3^)     | any dose level.  |
| Assay       | rats following     | formaldehyde |                  |
|             | formaldehyde       | by           |                  |
|             | inhalation.        | inhalation   |                  |
|             | Toxicol Lett       | for 6        |                  |
|             | 21:241-246.        | hours/day    |                  |
|             |                    | for 5 days.  |                  |
|             | **Open             | Blood was    |                  |
|             | Literature**       | 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)       |                  |
+-------------+--------------------+--------------+------------------+
| In vitro    | Craft, T.R., E.    | 0, 15, 30,   | **Positive**     |
| human       | Bermudez, and T.R. | 50, 125, or  |                  |
| l           | Skopek (1987)      | 150uM        | The 15, 30, and  |
| ymphoblasts | Formaldehyde       |              | 50 uM treatments |
|             | mutagenesis and    | Human        | resulted in no   |
|             | formation of       | Lymphoblasts | significant      |
|             | DNA-protein        | (4x 10\^5    | difference in    |
|             | crosslinks in      | cells/mL)    | growth rate      |
|             | human lymphoblasts |              | compared to      |
|             | in vitro. Mutation | Formaldehyde | control values;  |
|             | Research 176:      | (37% w/w     | the 125 uM       |
|             | 147-155.           | 10-15%       | and150 uM        |
|             |                    | methanol)    | treatments       |
|             | **Open             |              | resulted in      |
|             | Literature**       |              | approximately    |
|             |                    |              | 30% and 20%      |
|             |                    |              | survival,        |
|             |                    |              | respectively.    |
|             |                    |              | Single           |
|             |                    |              | treatments of    |
|             |                    |              | various          |
|             |                    |              | concentrations   |
|             |                    |              | of formaldehyde  |
|             |                    |              | resulted in a    |
|             |                    |              | nonlinear        |
|             |                    |              | increase in      |
|             |                    |              | induced mutant   |
|             |                    |              | fraction at the  |
|             |                    |              | thymidine kinase |
|             |                    |              | locus with       |
|             |                    |              | increasing slope |
|             |                    |              | above 125 uM.    |
|             |                    |              | 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       |
|             |                    |              | form             |
|             |                    |              | aldehyde-induced |
|             |                    |              | mutations, but   |
|             |                    |              | at a lower rate  |
|             |                    |              | than if a single |
|             |                    |              | 150uM treatment  |
|             |                    |              | was given at one |
|             |                    |              | time.            |
+-------------+--------------------+--------------+------------------+
| In vitro    | Liber, HL;         | Liber et al. | Northern blot    |
| human       | Benforado, K;      | (1989)       | analysis showed  |
| l           | Crosby, RM; et al. | followed up  | that the point   |
| ymphoblasts | (1989)             | the findings | mutations fall   |
|             | Fo                 | of Crosby et | into four        |
|             | rmaldehyde-induced | al. (1988)   | categories;      |
|             | and spontaneous    | by           | normal size and  |
|             | alterations in     | performing   | amount of RNA,   |
|             | human hprt DNA     | Northern     | normal size but  |
|             | sequence and mRNA  | blot and     | reduced amounts  |
|             | expression. Mutat  | sequence     | of RNA, reduced  |
|             | Res 226:31-37.     | analysis on  | size and amounts |
|             |                    | the 16       | of RNA, and no   |
|             | **Open             | induced and  | RNA. Sequence    |
|             | Literature**       | 10           | analysis of      |
|             |                    | spontaneous  | recombinant DNAs |
|             |                    | mutants not  | from HRPT mRNA   |
|             |                    | showing      | in               |
|             |                    | deletions.   | compound-induced |
|             |                    |              | mutants showed a |
|             |                    | Human        | preferential AT  |
|             |                    | Lymphoblasts | to CG            |
|             |                    |              | transversion at  |
|             |                    | Purity: 37%  | a single site,   |
|             |                    |              | with other       |
|             |                    |              | changes          |
|             |                    |              | represented to a |
|             |                    |              | lesser degree.   |
+-------------+--------------------+--------------+------------------+
| Other       | Graves, RJ;        | DNA sequence | Single-base pair |
|             | Trueman, P; Jones, | analysis of  | transversions,   |
|             | S; Green, T.       | formalde     | including three  |
|             | (1996) DNA         | hyde-induced | AT to TA at      |
|             | sequence analysis  | HRPT         | position 548 of  |
|             | of methylene       | mutations    | exon 8, one GC   |
|             | chloride-induced   |              | to TA, and two   |
|             | HPRT mutations in  | Chinese      | AT to CG         |
|             | Chinese hamster    | Hamster      | transversions at |
|             | ovary cells:       | Ovary Cell   | other sites.     |
|             | Comparison with    |              |                  |
|             | the mutation       | Purity: 40%  |                  |
|             | spectrum obtained  |              |                  |
|             | for                |              |                  |
|             | 1,2-dibromoethane  |              |                  |
|             | and formaldehyde.  |              |                  |
|             | Mutagenesis        |              |                  |
|             | 11:229-233.        |              |                  |
|             |                    |              |                  |
|             | **Open             |              |                  |
|             | Literature**       |              |                  |
+-------------+--------------------+--------------+------------------+
| Other       | Blackburn, GR;     | Forward      | Formaldehyde     |
|             | Dooley, J, III;    | mutation     | induced forward  |
|             | Schreiner, CA; et  | assay        | mutations to     |
|             | al. (1991)         |              | tr               |
|             | Specific           | Mouse        | ifluorothymidine |
|             | identification of  | lymphoma     | resistance both  |
|             | for                | L5178Y tk+/- | in the absence   |
|             | maldehyde-mediated | cells        | and presence of  |
|             | mutagenicity using |              | rat liver S9     |
|             | the mouse lymphoma | Purity: 37%  | (higher          |
|             | L5178Y TK positive | (w/w)        | concentrations   |
|             | negative assay     | aqueous      | required for     |
|             | supplemented with  | solution     | effect with S9). |
|             | formaldehyde       | (formalin)   | Both toxicity    |
|             | dehydrogenase. In  |              | and mutagenicity |
|             | Vitro Toxicology   |              | were abolished   |
|             | 4:121-132.         |              | when             |
|             |                    |              | formaldehyde     |
|             | **Open             |              | dehydrogenase    |
|             | Literature**       |              | was incorporated |
|             |                    |              | in the exposure  |
|             |                    |              | medium.          |
+-------------+--------------------+--------------+------------------+