![](media/image1.png)

**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, DC 20460**

OFFICE OF

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

> March 31, 2008

**MEMORANDUM:**

**Subject:** Formaldehyde: Toxicology Disciplinary Chapter for the
Registration Eligibility Decision (RED) Document.

**To:** Sharon Carlisle, Chemical Review Manager

Antimicrobials Division

**From:** Timothy F. McMahon, Ph.D., Senior Toxicologist

Antimicrobials Division

Attached is the Toxicology disciplinary chapter for formaldehyde for the

Reregistration Eligibility Decision Document.

**Table of Contents**

**1.0 Hazard
Characterization**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...4

**2.0 Toxicology
Data**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....10

**3.0 Data
Gaps**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...11

**4.0 Hazard
Assessment**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...11

**4.1 Acute
Toxicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...11

**4.2 Subchronic
Toxicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....12

**4.3 Prenatal Developmental
Toxicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....19

**4.4 Reproductive
Toxicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....21

**4.5** **Chronic
Toxicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....22

**4.6
Carcinogenicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...24

**4.7 Combined Chronic
Toxicity/Carcinogenicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...33

**4.8
Mutagenicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....34

**4.9
Neurotoxicity**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....43

**4.10 Metabolism and
Pharmacokinetics**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....45

**4.11 Special
Studies**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....46

**5.0 Toxicity End Point
Selection**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...67

**5.1 Summary of Toxicological Doses and
Endpoints**\...\...\...\...\...\...\...\.... \...\.....67

2.  **Dermal
    Absorption**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...67

> **5.3 Classification of Carcinogenic
> Potential**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....67

**6.0 FQPA
Considerations**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....69

**7.0 Summary of toxicological doses and
endpoints**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...70

**8.0 Toxicity Profile
Tables**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....71

**9.0
References**\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...94

**1.0 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.

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 (Kerns et al., 1983), 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. 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.

In a chronic toxicity study conducted by Battelle, Pacific Northwest
laboratories B6C3F1 mice (5/sex/group) were exposed to one of five
concentrations of vaporized formaldehyde for a period of 6 hours per day
at target concentrations of 15, 25, 50, 100, and 200 ppm (18.59, 30.98,
61.96, 123.93, and 247.85 mg/m^3^). Mild supportive 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. Male and females rats exposed at 15
ppm formaldehyde exhibited increased bone marrow hyperplasia beginning
at 20 months It is not known if bone marrow hyperplasia may be
indicative of a myeloproliferative or lymphoproliferative disorder, or a
regenerative response to gross tissue injury at the point of entry.
Squamous cell carcinoma (SCC) was also observed at the two highest dose
levels in this study.

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 provided 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. Significant increases in relative risk for
lymphohematopoietic cancer were observed primarily for myeloid leukemia
and Hodgkin's disease and for the peak exposure and average intensity
exposure metrics. For the nasopharyngeal cancers, significant trends
were observed for the cumulative and peak exposure metrics.

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 be 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 increase 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).

**2.0 TOXICOLOGY DATA**

Number range CHAPTERThe available toxicology data for Formaldehyde is
listed below.

Table 1. Toxicology Data for Formaldehyde

+--------------------------------------+-----------+---------+--------+
| **Test**                             | **Te      |         |        |
|                                      | chnical** |         |        |
+======================================+===========+=========+========+
|                                      | **MRID**  | **Req   | *      |
|                                      |           | uired** | *Satis |
|                                      |           |         | fied** |
+--------------------------------------+-----------+---------+--------+
| 870.1100 Acute Oral Toxicity         | 00058054, | yes     | yes    |
|                                      | 00065508  |         |        |
| 870.1200 Acute Dermal Toxicity       |           | yes     | yes    |
|                                      | 00058054, |         |        |
| 870.1300 Acute Inhalation            | 00065508, | yes     | yes    |
|                                      | 00159395  |         |        |
| 870.2400 Primary Eye Irritation      |           | yes     | yes    |
|                                      | Open      |         |        |
| 870.2500 Primary Dermal Irritation   | L         | yes     | yes    |
|                                      | iterature |         |        |
| 870.2600 Dermal Sensitization        |           | yes     | yes    |
|                                      | 00058054, |         |        |
|                                      | 00065508, |         |        |
|                                      | 00159395  |         |        |
|                                      |           |         |        |
|                                      | 00058054, |         |        |
|                                      | 00065514, |         |        |
|                                      | 00159392  |         |        |
|                                      |           |         |        |
|                                      | 40161103, |         |        |
|                                      | Open      |         |        |
|                                      | L         |         |        |
|                                      | iterature |         |        |
+--------------------------------------+-----------+---------+--------+
| 870.3100 90-day oral (Rodent)        | 00124677, | yes     | yes    |
|                                      | 00134114, |         |        |
| 870.3150 90-day oral (Non-rodent)    | Open      | yes     | yes    |
|                                      | L         |         |        |
| 870.3250 90-Day Dermal (Rat)         | iterature | yes     | no     |
|                                      |           |         |        |
| 870.3465 90-Day Inhalation (Rat)     | Open      | no      | yes    |
|                                      | L         |         |        |
|                                      | iterature | yes     |        |
|                                      |           |         |        |
|                                      | \-        |         |        |
|                                      |           |         |        |
|                                      | 00082134, |         |        |
|                                      | 00149755, |         |        |
|                                      | Open      |         |        |
|                                      | L         |         |        |
|                                      | iterature |         |        |
+--------------------------------------+-----------+---------+--------+
| 870.3700 Developmental Toxicity      | 00082136, | yes     | yes    |
| (Rat)                                | 00123769, |         |        |
|                                      | 00123770, | yes     | no     |
| 870.3700 Developmental Toxicity      | 00164652, |         |        |
| (Rabbit)                             | Open      | yes     | yes    |
|                                      | L         |         |        |
| 870.3800 Reproduction                | iterature |         |        |
|                                      |           |         |        |
|                                      | \-        |         |        |
|                                      |           |         |        |
|                                      | 00143291, |         |        |
|                                      | Open      |         |        |
|                                      | L         |         |        |
|                                      | iterature |         |        |
+--------------------------------------+-----------+---------+--------+
| 870.4100a Chronic (Rodent)           | Open      | yes     | yes    |
|                                      | L         |         |        |
| 870.4100b Chronic (Non-rodent)       | iterature | no      | yes    |
|                                      |           |         |        |
| 870.4200a Carcinogenicity (Rat)      | \-        | yes     | yes    |
|                                      |           |         |        |
| 870.4200b Carcinogenicity (Mouse)    | 00143288, | yes     |        |
|                                      | Open      |         |        |
|                                      | l         |         |        |
|                                      | iterature |         |        |
|                                      |           |         |        |
|                                      | Open      |         |        |
|                                      | L         |         |        |
|                                      | iterature |         |        |
+--------------------------------------+-----------+---------+--------+
| 870.5100 Mutagenicity -- Bacterial   | 00132156, | yes     | yes    |
| Reverse Gene                         | 00132157, |         |        |
|                                      | Open      | yes     | no     |
| Mutation assay                       | L         |         |        |
|                                      | iterature | yes     | yes    |
| 870.5385 Mutagenicity -- Bone marrow |           |         |        |
| chromosome                           | \-        |         |        |
|                                      |           |         |        |
| aberration test (Mouse)              | 00132169  |         |        |
|                                      |           |         |        |
| 870.5550 Mutagenicity -- Unscheduled |           |         |        |
| DNA synthesis                        |           |         |        |
|                                      |           |         |        |
| in primary rat hepatocytes           |           |         |        |
+--------------------------------------+-----------+---------+--------+
| 870.6200 90-day neurotoxicity        | Open      | yes     | yes    |
| (Mammal)                             | L         |         |        |
|                                      | iterature |         |        |
+--------------------------------------+-----------+---------+--------+
| 7485. Metabolism                     | Open      | yes     | yes    |
|                                      | L         |         |        |
| 870.7600 Dermal penetration          | iterature | yes     | yes    |
|                                      |           |         |        |
|                                      | Open      |         |        |
|                                      | L         |         |        |
|                                      | iterature |         |        |
+--------------------------------------+-----------+---------+--------+

**3.0 DATA GAPS**

90-day dermal toxicity study (rodent)

Developmental toxicity in non --rodents

Mutagenicity -- Bone marrow chromosome aberration test (mouse)

**4.0 HAZARD ASSESSMENT**

1.  **Acute Toxicity**

[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 2.

+--------+-----------------------+---------+----------------+--------+
| *      |                       |         |                |        |
| *Table |                       |         |                |        |
| 2.     |                       |         |                |        |
| Acute  |                       |         |                |        |
| To     |                       |         |                |        |
| xicity |                       |         |                |        |
| data   |                       |         |                |        |
| for    |                       |         |                |        |
| Formal |                       |         |                |        |
| dehyde |                       |         |                |        |
| tec    |                       |         |                |        |
| hnical |                       |         |                |        |
| a.i.** |                       |         |                |        |
+========+=======================+=========+================+========+
| **Gui  | **Study Type/ Test    | *       | **Results**    | **To   |
| deline | substance (% a.i.)**  | *MRID** |                | xicity |
| Nu     |                       |         |                | Cate   |
| mber** |                       | **      |                | gory** |
|        |                       | Number/ |                |        |
|        |                       | Cit     |                |        |
|        |                       | ation** |                |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Acute Oral -- Guinea  | 0       | LD~50~ = 260   | II     |
| 0.1100 | Pig                   | 0058054 | mg/kg          |        |
|        |                       |         |                |        |
| (      | Purity 37.3% -        |         |                |        |
| §81-1) | Formaldehyde          |         |                |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Acute Dermal -- Rat   | 0       | []{.mark}      | II     |
| 0.1200 |                       | 0058054 |                |        |
|        | Purity 37.3% -        |         | Number range   |        |
| (      | Formaldehyde          |         | CHAPTERLD~50~  |        |
| §81-2) |                       |         | = 300 mg/kg    |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Acute Dermal -- Rat   | 0       | []{.mark}      | III    |
| 0.1200 |                       | 0159395 |                |        |
|        | Purity 37.0% -        |         | LD~50~ \> 4.9  |        |
| (      | Formaldehyde          |         | mL/kg (4.53    |        |
| §81-2) |                       |         |                |        |
|        |                       |         | g/kg)          |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Acute Dermal --       | 0       | []{.mark}      | II     |
| 0.1200 | Rabbit                | 0058054 |                |        |
|        |                       |         | Number range   |        |
| (      | Purity 37.3% -        |         | CHAPTERLD~50~  |        |
| §81-2) | Formaldehyde          |         | = 240 mg/kg    |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Acute Dermal -- Dog   | 0       | Number range   | II     |
| 0.1200 |                       | 0058054 | CHAPTERLD~50~  |        |
|        | Purity 37.3% -        |         | = 550 mg/kg    |        |
| (      | Formaldehyde          |         |                |        |
| §81-2) |                       |         |                |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Acute Inhalation --   | See     |                |        |
| 0.1300 | Mouse and Rat         | Open    |                |        |
|        |                       | Lit     |                |        |
| (      |                       | erature |                |        |
| §81-3) |                       | studies |                |        |
|        |                       | in      |                |        |
|        |                       | T       |                |        |
|        |                       | oxicity |                |        |
|        |                       | Profile |                |        |
|        |                       | for     |                |        |
|        |                       | Forma   |                |        |
|        |                       | ldehyde |                |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Primary Eye           | 0       | Severe eye     | I      |
| 0.2400 | Irritation            | 0058054 | irritant       |        |
|        |                       |         |                |        |
| (      | Purity 37.3% -        |         |                |        |
| §81-4) | Formaldehyde          |         |                |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Primary Dermal        | 0       | Formation of   | I      |
| 0.2500 | Irritation            | 0058054 | vesicles with  |        |
|        |                       |         | superficial    |        |
| (      | Purity 37.3% -        |         | necrosis or    |        |
| §81-5) | Formaldehyde          |         | nodules.       |        |
+--------+-----------------------+---------+----------------+--------+
| 87     | Dermal Sensitization  | 4       | Extreme        | NA     |
| 0.2600 | -- Guinea pigs        | 0161103 | Sensitizer     |        |
|        |                       |         |                |        |
| (      | Purity 40.0% -        |         |                |        |
| §81-6) | Formaldehyde          |         |                |        |
+--------+-----------------------+---------+----------------+--------+

NA -- Not Applicable

**4.2 Subchronic Toxicity**

[Adequacy of database for Subchronic Toxicity]{.underline}: The database
for subchronic toxicity consists of guideline and open literature
studies.

**870.3100 Subchronic (90-day oral) Toxicity -- Rat**

In one 90-day oral toxicity in the rat (MRID 00124677) formaldehyde (37%
a.i.) was administered orally at 0, 0.3, 0.6, 1.2 or 2.4 % to 10 male
Holtzman rats/dose. A **NOAEL was established at 0.3% while the LOAEL
was 0.6%**, based on irritability, weight loss, hair loss, yellowing of
teeth, and decreased food consumption.

Rats exposed to concentrations of 0.6% formaldehyde and higher exhibited
dose-related increases in irritability, disability, hair loss, and
yellowing of teeth and dose-related decreased food consumption. Growth
rates significantly different from controls are expected at formaldehyde
concentrations ≥ 0.50 %, believed due to decreased food consumption.

**870.3100 Subchronic (28-day oral) Toxicity -- Rat**

In a 28-day oral toxicity study in the rat (MRID 00134114), formaldehyde
(60% a.i.) was administered to 10 male Sprague-Dawley rats/dose at
concentrations of 0, 79, 158 or 316 µg/kg/day, once daily, 5 days/week
for four weeks.

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

One rat exposed to158 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 Subchronic (90-day oral) Toxicity -- Rat**

In an oral subchronic toxicity study conducted by Johannsen et al.
(1986) Groups of albino Sprague-Dawley rats (15/sex) were administered
the equivalent of 0, 50, 100, or 150 mg/kg-day paraformaldehyde (95 %
a.i.) in their drinking water for 91 consecutive days. Rats were
observed at frequent intervals for behavioral reactions. Body weights
and food and water intake were recorded on a weekly basis. Hematology
(HCT, Hb, total and differential leukocyte counts), clinical chemistry
\[blood sugar, BUN, ALP, glutamic oxalacetic transaminase (GOT),), and
urine analyses (color, appearance, pH, specific gravity, sugar, protein,
and microscopic elements) were conducted on 10 male and 10 female rats
selected from each test group. Tissue weights were recorded for the
adrenals, gonads, hearts, kidneys, livers, lungs, and thyroids.
Histopathology was performed on a set of over 20 tissues and organs from
rats in the high-dose and control groups.

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

A s**ystemic toxicity NOAEL of 50 mg/kg/day for males and 100 mg/kg/day
for females was established while the systemic NOAEL was set at 100
mg/kg/day for males and 150 mg/kg/day for females**, based on decreased
body weight gain.

**870.3100 Subchronic (90-day oral) Toxicity -- Rat**

Til et al. (1988) evaluated the oral toxicity of formaldehyde and
acetaldehyde in a subacute study in Wistar (Cpb:WU; Wistar random) rats.
Groups of rats (10/sex/dose) were exposed to acetaldehyde or
formaldehyde at 0, 25, 125, and 625 mg/kg-day or 0, 5, 25, and 125
mg/kg-day in drinking water for 4 weeks. The control group was comprised
of 20 rats of each sex, and, to account for potential effects of
decreased water consumption in treated animals, an additional control
group of 10 male and 10 female rats was given drinking water in an
amount equal to the amount of liquid consumed by the group given the
highest dose. Fresh solutions of test concentrations were prepared
weekly and stored at 4 ºC until used. Endpoints examined included food
and water intake, body weight, daily observations for condition and
behavior, organ weights, hematological and clinical chemistry
parameters, urinalysis, gross pathology, and histopathology. Weights
were recorded for all major tissues. Histopathological examination was
restricted to the established major target tissues: liver, kidneys, GI
tract, and nose (six standard cross sections). Examination of the GI
tract was performed in all dose groups and included the tongue,
esophagus, and stomach. Histopathology for the other tissues was
performed on high dose and control animals.

"The rats appeared to be healthy throughout the study, and no effects on
growth occurred despite significant decreases in food and water intake
that occurred at the high dose (125 mg/kg-day). Yellow discoloration of
the fur occurred in the rats on the high dosage from week 3 onwards.
There were no significant changes in hematology among the exposed groups
except for slight (not statistically different) increases in packed cell
volumes in the water-restricted group and in high-dose males. The
high-dose groups of the formaldehyde-exposed and in the water-restricted
controls had slightly increased urine density, but again this was not
statistically significant. Plasma TP and ALB levels were decreased in
the males of the highest-dose group. No changes in tissue organ weights
occurred with the exception that relative kidney weights were slightly
increased in the females of the high-dose group. Gross pathological
findings were restricted to the GI tract and revealed a thickening of
the limiting ridge of the forestomach in all animals exposed at the
highest dose that was accompanied by a yellowish discoloration of the
mucosa. These latter changes were not observed in the
acetaldehyde-exposed animals. Treatment-related histopathological
changes were seen in the GI tract only. As shown in Table 5-29, slight
(8/20) or moderate (12/20) focal hyperkeratosis of the forestomach and
slight focal atrophic gastritis occurred in animals of the high dose
groups only. One female had moderate focal papillomatous hyperplasia. No
histopathological changes were observed in any animals of the lower dose
groups. The study established a LOAEL and NOAEL for epithelial changes
in the GI tract of male and female Wistar rats exposed to formaldehyde
in drinking water of 125 mg/kg-day and 25 mg/kg-day, respectively. "

**870.3150 Subchronic (90-Day oral) Toxicity in nonrodents -- Dog**

In a 90-day oral toxicity study in non rodents (Johannsen et al., 1986),
paraformaldehyde (95% a.i., aqueous) was administered to four Beagle
dogs/sex/dose at doses of 0, 50, 75, or 100 mg/kg/day.

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

The **NOAEL was 75 mg/kg/day while the LOAEL was established to be 100
mg/kg/day** for both males and females, based on reduced weight gain.

**870.3465 Subchronic (90-Day Inhalation) Toxicity**

An earlier cross-species study examined changes in lung tissue resulting
from continuous exposure but did not evaluate effects on the nasal
mucosa (Coon et al., 1970). Animals were exposed to 3.7 ppm formaldehyde
(4.6 mg/m3) for 90 days. Five species of animals were studied: male and
female Sprague-Dawley and Long-Evans derived rats (15), male and female
Princeton-derived guinea pigs (15), male New Zealand albino rabbits
(three), male squirrel monkeys (Saimiri sciureus) (three), and purebred
male beagle dogs (two). Blood samples were taken for hemoglobin (Hb)
concentration, hematocrit (HCT), leukocyte counts, and serum levels of
blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine
aminotransferase (ALT), alkaline phosphatase (ALP), and LDH. Sections of
heart, lung, liver, kidney, and spleen were fixed and examined from each
species (details of method not provided). Brain, spinal cord, and
adrenal tissue also were examined in monkeys and dogs as well as thyroid
from dogs. Liver and kidney sections were stained for reduced
nicotinamide adenine dinucleotide, lactate, isocitrate, and
ß-hydroxybutyrate. Tissue sections of the nasal mucosa were not examined
in this study.

Hematological parameters were unaffected by formaldehyde treatment. The
lung tissue of all species exhibited interstitial inflammation after 90
days of formaldehyde exposure (detailed description not provided).
Formaldehyde-treated rats and guinea pigs also had focal chronic
inflammation in heart and kidney tissue sections. However, the authors
were uncertain whether the observed changes to heart and kidney were due
to formaldehyde exposure.

**870.3465 Subchronic (6-Week Inhalation) Toxicity**

In a 6-Week inhalation toxicity study (MRID 00149755), Fisher 344 rats
-- 10/sex/dose; Syrian golden hamsters -- 10/sex/dose; and Cynomolgous
monkeys -- 6 males/dose, were administered formaldehyde (4.96% a.i.) at
concentrations of 0, 0, 0.20, 1.00, or 3.00 ppm equivalent to 0, 0,
0.19, 0.98 and 2.95 ppm, respectively, for 26 weeks.

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

[Body weight]{.underline}

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

[Organ weight]{.underline}

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

[Gross and Microscopic Pathology]{.underline}

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

**870.3465 Subchronic (90-Day Inhalation) Toxicity - Rat**

In a 90-Day inhalation toxicity study (Woutersen et al., 1987), male and
female albino SPF Wistar rats (10/group) were exposed to 0, 1, 10, or 20
ppm formaldehyde (0, 1.23, 12.3, or 24.6 mg/m3), 6 hours/day, 5
days/week for 13 weeks. Rats were checked daily and weighed weekly.
During week 13, blood samples were taken for Hb, packed cell volume, RBC
count, and a differential count of leukocytes. Urine samples were taken
for density, volume, pH, protein, glucose, occult blood, ketones, and
appearance. At sacrifice, blood samples were taken and analyzed for ALB,
creatinine, glucose, TP, BUN, and the enzyme activities (AST, ALT, and
ALP). GSH and protein content were determined in liver homogenates.
Organs were examined and weighed: adrenals, brain, heart, kidneys,
liver, lungs, ovaries, pituitary, spleen, testes, thymus, and thyroid.
Three longitudinal sections of lungs, trachea, and larynx and six
standard cross sections of the nose were taken for microscopic
examination. Two rats per exposure group were similarly treated for 3
days and sacrificed 18 hours later, and nasoturbinates were dissected to
measure cell proliferation. Nasoturbinates were removed, cultured with
\[3H\]-thymidine for 2 hours, and processed for autoradiography.

No gross pathological changes were seen upon autopsy, but body weights
decreased in the both male and female rats at the 20 ppm treatment
level. Of the organs weighed, 6 of 11 organs had significantly increased
relative rates in male rats exposed to 20 ppm formaldehyde (not
detailed). Relative brain weight was increased in female rats at the
same treatment level.

Clinical chemistry parameters of liver and kidney function and
hematological parameters were also measured after the 13-week treatment
by Woutersen et al. (1987). Compared to controls, activities of AST,
ALT, and ALP were significantly elevated in plasma from the 20 ppm
treated male rats (by 124%, 132%, and 126%, respectively, p\<0.05).
Total plasma protein was reduced to 95% of controls in the same animals.
Although there was an observed increase in BUN in male rats treated with
1 ppm, this was not considered a treatment effect. Furthermore, no
statistically significant differences were seen for these parameters in
female rats at any concentration level. Likewise, plasma ALB, plasma
creatinine, plasma glucose, total liver protein, GSH, and relative liver
weight were unchanged in all treatment groups.

Cell proliferation was measured in the respiratory epithelium of rats
treated for 3 successive days to the same treatment levels of
formaldehyde, 0, 1, 10, and 20 ppm. There was an increase of 37.6% in
\[3H\]-thymidine incorporation (indicating proliferation) in visibly
metaplastic epithelium resulting from exposure to 20 ppm formaldehyde,
compared to a level of 2.8% seen in unaffected tissue. However, there
were only two rats per treatment level.

Statistically significant increases were seen in focal respiratory
epithelial hyperplasia and keratinization in both male and female rats
at the highest treatment level (20 ppm). Male rats also had
statistically significant increases in observed respiratory epithelial
squamous metaplasia, focal olfactory epithelial thinning, and rhinitis.
Both male and female rats treated with 10 ppm formaldehyde showed
statistically significant increases in squamous metaplasia,

hyperplasia, and keratinization of the respiratory epithelium.

Disarrangement of the respiratory epithelium was only significantly
increased in female rats, but this change was observed at both the 10
ppm and 20 ppm treatment levels. Although some lesions were observed in
animals treated with 1 ppm formaldehyde, their incidences were not
statistically significant and the findings equivocal. A systemic
toxicity **NOAEL was established at 1.2 mg/m^3^ and the LOAEL was fixed
at 12 mg/m^3^,** based on 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 Subchronic (90-Day Inhalation) Toxicity**

Appelman et al. (1988) studied the effects of bilateral intranasal
electrocoagulation damage on susceptibility to inhaled formaldehyde in
male SPF Wistar (Cpb: WU) rats. Rats were exposed 6 hours/day, 5
days/week for 13 or 52 weeks to 0, 0.1, 1.0, or 10 ppm (0, 0.12, 1.24,
or 12.4 mg/m^3^) formaldehyde. These concentrations were chosen because
the various short-term studies performed in this laboratory showed that
formaldehyde was non-cytotoxic to the nasal mucosa at levels of 0.3,
1.0, and 2.0 ppm, slightly cytotoxic at 3 and 4 ppm, and strongly
cytotoxic at 10 and 20 ppm (Woutersen et al., 1987; Zwart et al., 1988;
Wilmer et al., 1987). Further, because nasal tumors have only been found
at exposure concentrations that also induced severe degenerative,
hyperplastic, and metaplastic changes in the nasal epithelium (Squire
and Cameron, 1984; Griesemer et al., 1985), Feron et al. (1984) and the
investigators at the TNO-CIVO Toxicology and Nutrition Institute
postulated that formaldehyde at a subcytotoxic concentration was only a
very weak initiator without promoting activity. Appelman et al. (1988)
used an electrocoagulation method in this study to evaluate if damage to
the mucosa followed by compensatory cell proliferation might render the
epithelium vulnerable to subcytotoxic levels of formaldehyde. One half
of the rats used in the study (10/group) were damaged bilaterally and
then subjected to the first 6-hour exposure to formaldehyde at
approximately 20--26 hours after the electrocoagulation procedure. Ten
undamaged rats/group were also exposed at each concentration for either
13 or 52 weeks.

General condition and behavior was monitored daily. Individual body
weights were recorded at the start of exposure, once weekly during the
first month, and monthly thereafter. Blood samples were drawn on all
interim sacrifice rats to measure plasma ALB and TP, and the activities
of AST, ALT, and ALP. Blood samples drawn on rats of the 53-week
sacrifice were examined for Hb, PCV, and differentials. Urine samples
collected at the second sacrifice were examined for volume, density, pH,
protein, glucose, occult blood, and appearance. The livers of all
animals were weighed. The left lateral lobe of each liver was used to
determine hepatic protein and GSH content in postmitochondrial
fractions. Additional organ weights obtained for animals in the last
sacrifice included adrenals, brain, heart, kidneys, lungs, pituitary,
spleen, testes, thymus, and thyroid. Histopathological examination
included six standard cross-section levels in the nose, livers of all
rats killed at 14 weeks and of all control and 10 ppm exposed rats
killed in week 53, larynxes, tracheas, and lungs of all rats of the
control and 10 ppm exposed rats killed in week 53, and organs and
tissues of control and 10 ppm exposed rats with an undamaged nasal
mucosa killed in week 53.

Yellow discoloration of the fur occurred in all animals of the two
highest exposure groups. Growth retardation was observed in the animals
killed with or without damaged noses after 2 weeks exposure to 10 ppm
formaldehyde. No toxicologically significant findings in the body
weights or organ weights of any animals in the other exposure groups
were observed. No relevant differences between groups were found in any
of the hematological or urinary parameters with the exception of
frequent oliguria (p \< 0.05) in the top exposure group without nasal
coagulation and killed in week 53. Three-way ANOVA revealed a
significant increase in TP content of the liver in rats with damaged
noses as compared to rats with undamaged noses, and there was a
significant negative correlation between the formaldehyde exposure level
and TP in these same rats. Hepatic GSH were positively correlated with
both nasal damage and age of the animals.

The systemic toxicity **NOAEL was established at 1.24 mg/m^3^ while the
LOAEL was 12.4 mg/m^3^,** based on body weight retardation, incidence of
oliguria, and incidence of lesions of the respiratory and olfactory
epitheliums for damaged and undamaged animals.

**870.3465 Subchronic (90-Day Inhalation) Toxicity -- Mice and Rat**

In a 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.

No adverse effects observed in the 4 ppm group. At 12.7 ppm, a decrease
in body weight and evidence of nasal erosion in two exposed rats was
observed. Ulceration and necrosis of the nasal mucosa seen at 38.6 ppm
resulted in termination of exposure after 2 weeks. **The systemic NOAEL
was 4 ppm (4.96 mg/m^3^, LDT) while the systemic LOAEL was established
to be 12.7 ppm (15.74 mg/m^3^)**, based on body weight decrease and
nasal erosion.

**870.3465 Subchronic (90-Day Inhalation) Toxicity**

In a 90-day inhalation toxicity study (Citation not available),
formaldehyde was administered to 25 rats at concentrations of 0.0098,
0.028, 0.82 or 2.4 ppm (0.012, 0.035, 1.03 and 2.97 mg/m^3^,
respectively).

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. The **systemic activity NOAEL was 0.028 ppm (0.035
mg/m^3^) and the Systemic LOAEL was 0.82 ppm (1.02 mg/m^3^)**, based on
proliferation of lymphocytes, histiocytes in the lungs, perivascular
hyperemia. The **cholinesterase (ChE) NOAEL was 0.82 ppm (1.02 mg/m^3^)
while the ChE LOAEL was 2.4 ppm (2.97 mg/m^3^),** based on a significant
decrease in cholinesterase activity at this dose level.

**4.3 Prenatal Developmental Toxicity**

[Adequacy of database for Prenatal Developmental Toxicity]{.underline}:
The database for developmental toxicity of formaldehyde is considered
incomplete with a developmental toxicity study in non-rodents being
unavailable. The database consists of three submitted and two open
literature studies in rodents.

**870.3700a Prenatal Developmental Toxicity Study -- Mouse**

Marks et al. (1980) carried out a developmental toxicity study of
formaldehyde in CD-1 mice in which 29-35 pregnant animals were gavaged
on GDs 6-15 with aqueous formaldehyde (containing 10-15% methanol) at
74, 148, and 185 mg/kg-day. Seventy-six controls were gavaged with water
alone. All dams were sacrificed on GD 18 and the number of implantation
sites in each uterine horn were counted. The high-dose of formaldehyde
was toxic to the dams, as indicated by the deaths of 22 of 34 mice
before GD 18. Thus, the dose of 148 mg/kg-day was a NOAEL for maternal
toxicity in this study. However, it is unclear to what extent an
estimated concurrent dose of up to 75 mg/kg-day methanol may have
contributed to this toxic response. To assess the developmental toxicity
of formaldehyde, live fetuses were weighed individually, sexed, and
examined for external, visceral, and skeletal malformations. Fetuses of
surviving high-dose dams and of those of other groups did not show an
increased incidence of malformations. Therefore, Marks et al. (1980)
concluded that formaldehyde did not induce fetal abnormalities and that
the 185 mg/kg-day dose level was a NOAEL for the developmental toxicity
of formaldehyde. Neither were the fetotoxic effects of methanol apparent
under the subject experimental conditions.

The maternal toxicity NOAEL was established to be **0 mg/kg/day and the
maternal toxicity LOAEL was 74 mg/kg/day, based on decreased body weight
gain.**

**870.3700a Prenatal Developmental Toxicity Study -- Rat**

Sallenfait et al. (1989) report a comprehensive and well-documented
developmental study in Sprague-Dawley rats. Pregnant rats were exposed
beginning on GD 6 in order to cover critical stages of development
(e.g., implantation and major organogenesis). Female Sprague-Dawley rats
(25/group) were exposed to 0, 5, 10, 20, or 40 ppm formaldehyde (0,
6.15, 12.3, 24.6, or 49.2 mg/m3), 6 hours/day on GDs 6--20. The onset of
pregnancy was determined by the presence of sperm in a vaginal smear.
Dams were exposed to formaldehyde in a dynamic flow chamber and
formaldehyde concentrations were determined to be 5.17 ± 0.51, 9.92 ±
0.88, 20.04 ± 0.88, and 38.96 ± 3.70, respectively. Dams were weighed on
GDs 0, 6, and 21 and sacrificed on day 21. Upon examination, uterine
weights, fetal weights, sex ratio, and the number of implantation and
resorption sites, live and dead fetuses were recorded. Fetuses were
examined for external malformations and cleft palate. One half of viable
fetuses were sectioned to assess soft-tissue alterations. The other half
were fixed, stained with Alizarin Red S, and examined for skeletal
alterations.

Body weight gain of dams and body weight of male and female fetuses were
reduced by exposure to 40 ppm formaldehyde to 49%, 78%, and 81% of
control values, respectively (p\<0.01) (Saillenfait et al., 1989).
Reduced weight gain in dams remained significantly decreased when
uterine weight was accounted for (p\<0.01). Mean fetal weight of male
pups was reduced at maternal exposures of 20 and 40 ppm formaldehyde
(5.53 g and 4.42 g versus 5.61 g in controls). Decreased fetal body
weight in females was only seen at 40 ppm (4.27 g versus 5.24 g in
controls.). All other pregnancy endpoints were unchanged by formaldehyde
exposure (e.g., uterine weight, implantation and resorption sites, live
fetuses, dead fetuses, and sex ratios). No major malformations were
noted in fetuses. Some minor soft tissues and skeletal anomalies such as
dilated ureter, missing sternebrae, extra fourteenth rib, and
rudimentary thirteenth rib (statistics not given), were reported.
However, these effects occurred at similar frequencies in control and
treatment groups. The incidence of delayed ossification of the thoracic
vertebrae was 8.7% in fetuses from the 40 ppm exposure group versus 1.8%
in controls. However, this difference was not statistically significant.
Overall, formaldehyde was not embryolethal or teratogenic in the studies
and only exhibited fetotoxic effects at exposures of 20 ppm and above.
These are levels where there was a significant decrease in fetal body
weight.

The maternal toxicity **NOAEL was 24.8 mg/m^3^ and the LOAEL was
established to be 49.6 mg/m^3^**, based on decreased body weight gain.
The developmental toxicity **NOAEL was 12.4 mg/m^3^ and developmental
toxicity LOAEL was established to be 24.8 mg/m^3^**, based on reduced
fetal weight gain.

**870.3700a Prenatal Developmental Toxicity Study -- Hamster**

Experiments by Overman (1985) were aimed at examining the compound's
potential for inducing systemic effects in laboratory animals via the
dermal route; in this case, the potential of topically applied
formaldehyde to induce teratological effects in the progeny of pregnant
Syrian golden hamsters. The shaved dorsal surfaces of lightly
anesthetized dams were treated with a single dose of 0.5 mL 37%
formaldehyde for a 2-hour period on any one of GDs 8, 9, 10, or 11,
after which the skin was washed thoroughly with water to remove any
remaining compound. Fetuses were dissected from sacrificed dams on GD
15, fixed in Bouin's solution, then examined for visceral malformations
or skeletal abnormalities**.** Treatment had no effect on maternal
weight gain. The treatment did not influence fetal C- R length. Mean
fetal weight was slightly increased in experimental animals, but the
difference was not statistically-significant. Two fetuses from the same
litter after treatment on day 8 were significantly smaller than their
litter mates (\>3 SD below mean). The same was true for 2 fetuses from
different litters after treatment on day 10. One fetus of normal size
treated on day 10 had a subcutaneous hemorrhage in the dorsal cervical
region. No skeletal malformations were found and no other malformations
were observed.

**4.4 Reproductive Toxicity**

[Adequacy of database for Reproductive:]{.underline} The database for
reproductive toxicity of formaldehyde is considered complete with one
study in the rat and one study in the dog.

**870.3550 Reproductive Toxicity - Dog**

In MRID (00143291) Hurni and Ohder tested the developmental toxicity of
formaldehyde in 9 to10 pregnant beagle dogs who received the compound in
the diet on GDs 4-56. Commercial grade formaldehyde (as a 40% solution)
was sprayed on the pellets prior to feeding. Each animal was allotted a
diet of 300 g of chow (reduced to 200 g 1 week prior to term) that was
promptly consumed (within 5-10 minutes) before the formaldehyde
volatilized appreciably. The concentrations of formaldehyde in the chow
were 0, 125, or 375 ppm, equivalent to doses of 0, 3.1, and 9.4
mg/kg-day, respectively. Dams were allowed to deliver normally and
weight gain, gestation length, the number of litters, litter size,
number of live pups, number of pups surviving through weaning, and pup
weights weekly for the first 8 weeks were monitored as indices of the
potential reproductive/developmental toxicity of formaldehyde. There
were no formaldehyde-related effects in any of the parameters other than
progressive pup weights, which were lower by group in litters of dams
exposed to formaldehyde. A developmental impact of formaldehyde was
evident in this strain of dog under the conditions of the experiment.
The pup weight decrements were 6.3% for the low-dose dams and 12% for
the high-dose. However, no internal or skeletal malformations were
observed in any of the 264 live-born and 20 still-born pups, suggesting
that formaldehyde had no developmental toxicity in beagles at ingested
concentrations as high as 9.4 mg/kg-day.

**870.3550 Reproductive Toxicity -- Rat**

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.

**4.5** **Chronic Toxicity**

**870.4100a Chronic Toxicity -- Rodent**

In a chronic toxicity study conducted by Battelle, Pacific Northwest
laboratories, B6C3F1

mice (5/sex/group) were exposed to one of five concentrations of
vaporized formaldehyde for a period of 6 hours per day for a total of
ten exposures. The target concentrations were 15, 25, 50, 100, and 200
ppm (18.59, 30.98, 61.96, 123.93, and 247.85 mg/m^3^).

Concentrations of 123.93 mg/m^3^ or greater produced 100% mortality. The
highly irritating nature of this chemical was evident microscopically in
all dose levels examined, ranging from minimal to mild supportive
rhinitis in the 18.59 mg/m^3^ dose level dose level, to necrosis and
sloughing of the mucosa in the turbinates, trachea, and proximal bronchi
in the 61.96 mg/m^3^ animals.

Differential weight gains of both male and female mice at 18.59, 30.98,
and 61.96 mg/m^3^ was significant as 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 Chronic Toxicity -- Rodent**

Kamata et al. (1997) evaluated the effects of inhaled formaldehyde in
male F344 (F344/DuCrj) rats (32/group) exposed for 28 months.
Formaldehyde exposure was generated by metering 37% formalin (containing
10% methanol) into a sprayer in a glass bottle and diluting with room
air. Concentration in the chamber was monitored twice daily by the
acetyl acetone method. Exposures were for 6 hours/day, 5 days/week at
nominal formaldehyde concentrations of 0, 0.3, 2.0, and 15 ppm. Actual
levels (mean ± SD) were 0, 0.3 ± 0.07, 2.17 ± 0.32, and 14.85 ± 2.22
ppm. Rats in the 0 ppm group were noted to inhale methanol at the same
concentration (4.2 ppm) as the 15 ppm group. A room control, no-exposure
group was also included in the study. All animals were observed for
clinical signs once a day during the study. Body weights and food
consumption were recorded weekly. Five animals per group were randomly
selected at the end of 12, 18, and 24 months and surviving animals at 28
months were sacrificed for hematological measurements \[Hb, RBCs, PCV,
MCV, mean corpuscular hemoglobin (MCH), MCHC and WBCs\], biochemical
determinations (TP, ALB, BUN, ALP, AST, ALT, glucose, albumin/globulin
ratio, phospholipids, triglycerides, and total cholesterol), and
pathological examinations. Wet weights were taken on brain, heart,
lungs, liver, kidneys, spleen, testes, and adrenal gland of each rat.
Histopathology was performed on all moribund or dead animals and those
at specified sacrifices on all gross lesions and the following tissues:
pituitary, thyroid, nasal cavity, trachea, esophagus, stomach, small and
large intestines, prostate gland, urinary bladder, muscle, femur,
sciatic nerve, spinal cord, and mesenteric lymph nodes.
Histopathological sections were obtained from five anatomical levels,
but these did not correspond to the typical levels taken in other
bioassays. Most notably, section Level B was anterior and not posterior
to the incisor teeth. The incidence data for nasal histopathology were
not reported with respect to section level location with the exception
that the nonproliferative lesions and tumors reported were described to
occur predominantly at Levels B and C.

Yellow discoloration of the coats occurred in animals exposed at the 2
and 15 ppm levels. Significant decreases in body weight and food
consumption were observed in the high concentration (15 ppm) group
throughout the exposure period. Mortality rates at the 28th month were
59.6% in the room control group, 45.5% in the 0 ppm group, 31.8% in the
0.3 ppm group, 55.9% in the 2 ppm group, and 88.3% in the 15 ppm group.
In the 15 ppm group, the first death occurred after 6 months and a total
of 20 rats died by the end of 24 months. Rats started to die from the
19th month in the 0 ppm group with a total of eight animals dying
spontaneously in that group by the end of the study. No abnormal
compound-related hematological findings were observed. A statistically
significant decrease in triglycerides was observed at the 12-month
sacrifice, and a similar trend (though not statistically significant)
was observed in animals at the high concentration (15 ppm) at the 18-
and 24-month sacrifices. Absolute liver weight was significantly reduced
in these same animals and the relative liver weight was decreased at the
18th month sacrifice. Relative adrenal weights were increased in the
animals exposed at the high concentration at the 12-month sacrifice. No
other remarkable observations were made.

Macroscopic and histopathological findings were limited to the nasal
cavity. Squamous cell metaplasia without epithelial cell hyperplasia was
increased in animals exposed at the 2 ppm level and was likely masked by
the proliferative lesions observed in the animals exposed at 15 ppm. It
was difficult to discern a duration-related trend in any of the data due
to the concurrent mortality. The total number (across all scheduled
sacrifices and unscheduled deaths) of proliferative lesions observed
with an increased incidence at the 15 ppm level included (\* indicates
significance at p \< 0.01 level): squamous cell metaplasia with
epithelial cell hyperplasia (29 %\*), epithelial cell hyperkeratosis (26
%\*), papillary hyperplasia (2%), SCC (13 %\*), and squamous cell
papillomae (3%). The total number of squamous cell metaplasia with
epithelial cell hyperplasia was also increased (7 %\*) in the 2 ppm
group but by only 4% in the 0.3 ppm group(not statistically
significant). These results are similar to those reported above for the
CIIT 2-year bioassays performed in F344 rats and are consistent with
those of Woutersen et al. (1989), who exposed Wistar rats for 28 months.
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.

The systemic toxicity **NOAEL was established to be 0.4 mg/m^3^ and the
LOAEL was established 2.5 mg/m^3^.**

6.  **Carcinogenicity**

[Adequacy of database for Carcinogenicity]{.underline}: The database for
carcinogenicity consists of one submitted and six open literature
studies.

**870.4200a Carcinogenicity -- Rat**

In a carcinogenicity study (MRID 00143288), rats were repeatedly
subjected to subcutaneous injections of 1 cm^3^ of an aqueous
formaldehyde solution at 0.6% to 0.8%. With 0.4% to 0.5% aqueous
formaldehyde solutions it was possible to inject subcutaneously once or
twice a week. Subcutaneous injections of 1 cm^3^ of a 0.4% aqueous
formaldehyde solution were continued on 10 rats once a week for about 1
year and three months.

0.6% to 0.8%: Necrosis, formation of an ulcer, while the area around the
injection spot formed a tuber which was very difficult to heal

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

**870.4200a Carcinogenicity -- Rat**

In a carcinogenicity study in male Fischer Rats, Tobe et al. (1985),
administered formaldehyde at concentrations of 0, 0.3, 2.0 or 15 ppm (0,
0.37, 2.48 or 18.59 mg/m^3^, respectively) in aqueous solution methanol,
6 hours/day, 5 days/week for 28 months. The exposure at 15 ppm was
tested for 24 months. A positive control -- 3.3 ppm methanol and a
nonexposure (NE) control were also used.

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

Recognizable tumors were observed in the 15 ppm group from the 420^th^
day onwards and tumors were recognized 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 Carcinogenicity -- Rat**

Takahashi et al. (1986) studied the effects of formaldehyde in an
initiation-promotion model of stomach carcinogenesis in male outbred
Wistar (Shizuoka Laboratory Center, Shizuoka) rats. Rats (n=17) were
given 100 mg/L of N-methyl-N¹-nitro-N-nitrosoguanidine (MNNG) in
drinking water and a diet supplemented with 10% sodium chloride for the
first 8 weeks as an initiation phase. This was followed by 0.5% formalin
in drinking water for 32 weeks as the promotion phase of the protocol. A
comparison group (n=10) was given stock water and diet without any
supplementation for the first 8 weeks followed by 0.5% formalin in
drinking water for 32 weeks. Animals were observed daily and weighed
once every 4 weeks. Histopathology was evaluated on the stomach and
other tissues in the peritoneal cavity.

Body weight gain was reduced by exposure to MNNG with sodium chloride,
and formaldehyde exposure during the promotion phase exacerbated this
effect. Histopathological investigations were restricted to the GI
tract. Formaldehyde was shown to statistically increase the incidence of
lesions in the forestomach and stomach in the animals initiated with
MNNG with sodium chloride as compared to controls receiving no
initiation. Increases in papilloma in the forestomach, adenomatous
hyperplasia in the fundus, and adenocarcinoma in the pylorus were
observed. Histopathology in the animals receiving formaldehyde alone for
weeks 9 through 32 showed only an increase in forestomach papillomas
without any lesions reported for the glandular stomach. The adenomatous
hyperplasia was defined as proliferative, noninvasive mucosal lesions,
and the adenocarcinomas as well differentiated and composed of typical
glandular structures demonstrating a tubular pattern and cellular or
structural atypism without metastasis. No definition of criteria for
papilloma diagnosis was provided. The findings in this study are
inconsistent with those of Til et al. (1989) who found no evidence of
carcinogenicity in a 2-year bioassay at comparable concentrations
(assuming 37% formaldehyde in formalin results in 0.19% formaldehyde in
this study). As discussed above, the differences may be due to
differences in the strains of rat or in the diagnostic criteria. The
lack of more than one test concentration precludes dose-response
analysis of this study and provides only a stand-alone LOAEL of 0.2%
formaldehyde in drinking water. The lack of consumption data precludes
an estimation of dose in mg/kg-day.

**870.4200b Carcinogenicity -- Mouse**

In a study conducted by Iversen (1986), the possible carcinogenic
potency of formaldehyde in classical skin painting experiments (at
concentrations comparable to those used in pathology laboratories) was
evaluated.

Formaldehyde was topically applied to the back skin of hairless hr/hr
Oslo mice. The animals were divided into five groups and the study
design was as follows: Group I -- 200 µL of a 1% solution of
formaldehyde (40% a.i.) in water was applied twice weekly. Group II -
200 µL of a 10% solution of formaldehyde (40% a.i.) in water was applied
twice weekly. Group III -- 51.2 µg of DMBA (Dimethylbenz(*a*)anthracene)
in 100 µL acetone was applied once initially and nine days later
followed with 200 µL of a 10% solution of formaldehyde (40% a.i.) in
water, the latter being applied twice weekly. Group IV - 51.2 µg of DMBA
in 100 µL acetone was applied once initially and nine days later
followed with 17 nmol of TPA (12-0-tetradecanoylphorbol-13-acetate), the
latter being applied twice weekly. 16 male and 16 female mice were
utilized for the first four groups and observed weekly for 60 weeks.
Group V -- 176 mice were treated with 51.2 µg DMBA once and given no
further treatment. The animals were observed once weekly for 80 weeks.

All animals in groups II and III (10% formaldehyde -- treated) were
autopsied and all organs, including the brain, were inspected for any
sign of pathology. Tissue pieces were fixed in buffered formaldehyde and
histological sections of the brain, nasal mucosa and lungs were
subsequently made. Any signs of carcinoma, papilloma or any other tumor
were observed for. Lungs were observed for inflammatory lesions and the
presence of any alveolar macrophages. The epithelium in the nasal mucosa
was investigated for possible metaplasia or dysplasia.

All animals in group I survived the whole experiment with one of them
developing an infected atheroma of the skin. Apart from this one
observation, there were no pathological lesions, either macroscopically
or microscopically. Animals in Group II generally had a slight
hyperplasia of the epidermis. A few animals had small skin ulcers or
scratches, and in two animals small nonspecific granulomas were observed
in the lungs. There were no signs of lesions in the brain or any other
organs in the animals belonging to this group. No signs of metaplasia or
dysplasia were seen in the nasal mucosa either. In group III one animal
died accidentally in week 26, but histologically only epidermal
hyperplasia was found. Three animals in the group had lung adenomas and
11 of 32 animals had neoplastic growths on the skin, altogether 3
squamous cell carcinomas and 22 papillomas i.e. 25 skin tumors. The
first three papillomas were observed in week 10 following treatment.
There was no evidence of brain or other tumors, nasal dysplasia and no
increase in number of alveolar macrophages. Group IV animals showed an
increase in mortality. At 20 weeks there were 80% surviving animals
which decreased to 40% by week 40. At termination (week 46), there were
only 11 animals surviving of the original 32. At week 20, all the
surviving animals in the group were papillomabearing. No carcinomas or
sarcomas were observed. Almost all of the 176 animals in group V
survived the experiment. Altogether 225 skin tumors developed on 85
animals, 6 of these being squamous cell carcinomas. Two animals
exhibited lymphosarcomas at autopsy.

Formaldehyde alone gave no tumors while there was a significant
enhancement effect of painting twice with 10% formaldehyde subsequent to
painting once with DMBA as compared to DMBA alone. There was no
significant difference between tumor yields in the two groups mentioned
above. There was a significant difference between DMBA followed by TPA
on the one hand, and the other two combined treated schedules on the
other. Neither 1% nor 10% formaldehyde in water applied topically twice
a week on the back skin of hairless mice had any observable carcinogenic
effect on any of the observed organs of mice. Mice painted with 51.2 µg
DMBA in acetone followed by 10% formaldehyde application, demonstrated a
significant tumor enhancement and shortened latency times.

**870.4200b Carcinogenicity -- Mouse**

This carcinogenicity study by Iversen (1988) is a repeat of an earlier
study (Iversen, 1986) conducted by the same author but in this case
topical applications of formaldehyde were evaluated using SENCAR mice,
an animal model bred for maximum sensitivity to chemical tumorigenesis.

A group of 16 male and 16 female SENCAR mice (Group A) were topically
administered 100 µL of reagent grade acetone on the skin of the back
twice a week. Another group of 32 animals (Group B) was treated with 200
µL 4% formaldehyde (10% formalin) in water twice a week. A third group
(Group C) was administered 51.2 µg DMBA in acetone once followed by 200
µL of 1% formaldehyde (2.5% formalin) twice weekly. A pooled group from
previous studies (Group D -- 176 mice) which had been treated with 51.2
µg DMBA was used as a historical control to compare with the SENCAR
mice. A control group (Group E -- 96 mice) was given a single
application of 51.2 µg DMBA in 100 mL acetone. The last group (Group F)
was administered 51.2 µg DMBA in acetone followed by 200 µL of 4%
formaldehyde (10% formalin) twice weekly.

The animals were observed for 58 weeks for skin tumors and all animals
were autopsied. Specimens were collected from all skin lesions and from
obvious pathological lesions observed in the internal organs. Tissue
pieces were fixed in 4% buffered formaldehyde and histological sections
made. Statistical assessments were made on the basis of the crude
incidence of skin tumors with the results being represented as tumor
rates (the percentage of tumor-bearing animals in relation to the number
of animals alive at the appearance of the first tumor related to time)
and tumor yields (the cumulative occurrence of all skin tumors related
to time) in all groups. Differences in tumor rates were assessed using
the method of Peto (1974) and differences in tumor yields were assessed
using the method of Gail et al. (1980). Final tumor yields were also
assessed with the chi-square method, which was also utilized to compare
differences between the groups with regards to lung adenomas and
malignant tumors.

There was no difference in mortality rates among the treatment groups.
There was a negligible tumor rate in SENCAR mice treated with acetone or
with 4% formaldehyde alone (Groups A and B). Group C (DMBA followed by
1% formaldehyde) produced 26% tumor bearing animals and the time to
tumors were slightly shorter (21 weeks versus 32 weeks before 50% of the
final tumor rates were reached) than those administered DMBA alone.
Group D (single application of 51.2 µg DMBA) animals produced 42% tumor-
bearing animals while Group F (DMBA followed by 4% formaldehyde)
produced 44% tumor-bearing animals and the average time to tumor seemed
to be somewhat shorter (20 versus 32 weeks) than seen in the group given
DMBA alone. There was a significantly higher tumor crop in the SENCAR
mice (Group E) than in the hr/hr Oslo mice (Group D). There was a very
significant difference in tumor rates between Groups A, B and Group E
while there was no difference in tumor rates between animals of Group E
when compared separately with Group C and Group F animals. There was a
very significant trend seen with DMBA followed by 4% formaldehyde as the
most effective tumorigenic protocol.

Tumor yields were found to be highest for animals in Group F (DMBA
followed by 4% formaldehyde) but were not statistically significant.
Tumor yield for animals in Group E (96 mice) were adjusted to correspond
with the number of mice in other groups and the results for tumor yields
were similar to those observed for tumor rates. Final number of tumors
was higher in Group F (51 tumors in 32 animals) compared to Group E (36
tumors in 32 animals). The difference however, was not significant
according to the chi-square method (χ^2^ = 1.7859 with 1 DF, 0.20 \> *p*
\> 0.10).

Three dermal fibromas and one lymphocytic lymphoma were found in Group
A, two lung adenomas occurred in Group B, one lung adenoma, one dermal
sarcoma, one lymphoma and one adenocarcinoma of the breast were found in
Group C, 14 squamous cell carcinomas of the skin per 32 animals were
found in Group E, three lymphomas and one lung adenoma were found in
Group F. The chi-square test showed only a suggestive difference between
Groups E and F as regards to skin malignancies (χ^2^ = 3.8065, 1 DF,
0.10 \> *p* \> 0.05). Hence, there was a slight tendency for
formaldehyde to reduce the number of skin carcinomas provoked by DMBA.

The experiment with SENCAR mice gave results similar to those observed
in the hr/hr Oslo strain (Iversen, 1986). Formaldehyde has no
tumorigenic effect of its own, but may slightly enhance DMBA induced
tumorigenesis, manifested in a tendency to shorten the latency period
(for tumor rates) and provoking a slightly, but not convincingly higher
number of tumors (tumor yield). In regard to malignant skin tumors,
formaldehyde tended to be anticarcinogenic.

**870.4200b Carcinogenicity -- Mouse**

In a study by Krivanek et al. (1983), formaldehyde in a 50:50 acetone:
water vehicle was tested for its ability to initiate and/or promote
tumorigenesis in CD-1 female mice. In addition, a repeated exposure skin
irritation pretest to determine irritating and nonirritating doses of
formaldehyde was also undertaken by the authors.

In the skin irritation pretest formaldehyde was applied to approximately
1 square inch of shaved skin on the back of 30 female CD-1 mice at
concentrations of 0.1 (0.1%), 0.5 (0.5%), 1.0 (1%), 2.0 (2%), 5.0 (5%)
or 10.0 (10%) mg/100 µL in a acetone: water mixture. The 0.1 and 0.5
mg/100 µL doses were applied daily, except for weekends, for three weeks
while all other doses were applied daily, except for weekends, for two
weeks. Skin responses were observed daily on weekdays.

Initiation treatment consisted of a single application of 5 mg
formaldehyde (10%) in 2.5 µg TPA (Phorbol myristate acetate) with the
control for this treatment being 50 µL acetone/2.5 µg TPA. Two weeks
subsequent, promotion treatments were initiated with the promoter
potential of formaldehyde being tested at concentrations of 0.1, 0.5 and
1.0 mg/150 µg BaP (Benz (*a*)pyrene). The dose used to test formaldehyde
as an initiator as well as promoter was 5 mg formaldehyde/1.0 mg
formaldehyde. The control for this group was 5 mg formaldehyde/100 µL
acetone. Promotion treatments were administered thrice weekly for 26
weeks to groups of 30 female CD-1 mice following which the animals were
held for an additional 26-week recovery period. Body weight
determinations were made biweekly during the promotion treatment and
monthly during the recovery period. Skin test sites were observed daily
during promotion and biweekly during the recovery period. Skin nodules
were chartered monthly while mortality was recorded upon occurrence.

Observations made during the skin irritation pre-test showed that the 10
mg dose produced moderate skin irritation after 2-4 applications,
characterized by drying and cracking of the skin (fissuring), sloughing
and papules. The 2.0 and 5.0 mg doses produced mild to moderate skin
irritation after 4-5 treatments while the 1.0 mg produced mild
irritation during the second week of treatment. The 0.5 mg dose level
exhibited slight skin irritation potential which was reversible after a
brief rest period. No skin irritation was observed in the 0.1 mg dose
group after three weeks of treatment. Based on the results of the skin
irritation pre-test, doses of 0.1, 0.5 and 1.0 mg formaldehyde were
selected for evaluating the promoter potential of formaldehyde.

Body weight curves for the initiation-promotion study indicate no
significant differences between the four representative groups:
acetone/TPA, BaP/TPA, 5 mg formaldehyde/TPA and 5 mg formaldehyde/1.0 mg
formaldehyde. Mortality was low in all but the positive control group
ranging from 2-5 per group. Eight positive control mice died or were
sacrificed [in]{.underline} [extremis]{.underline} due to large
ulcerated tumors. Skin nodules were seen in 3/27 mice in the acetone/TPA
group, 5/28 mice in the formaldehyde/TPA group and comparison of these
groups for initiator potential of formaldehyde revealed no significant
difference. In the positive control group (BaP/TPA) 29/29 mice had at
least one skin nodule. The incidence of nodules was 3/27 in the
BaP/acetone group, 7/27 in the BaP/0.1 mg formaldehyde group, 2/28 in
the BaP/0.5 mg of formaldehyde group and 1/25 in the Bap/1.0 mg
formaldehyde. However, Fisher's exact test analysis indicated no
statistical difference between these groups. There were no mice with
skin nodules in the formaldehyde/formaldehyde and formaldehyde/acetone
groups. In addition, the positive control group BaP/TPA exhibited the
earliest time-to-nodule onset when compared to other groups. Only
animals in the positive control group developed malignant tumors --
squamous cell carcinomas. There were no statistically significant
differences between the test and control groups as indicated by
Fischer's Exact Test.

Minimally irritating solutions of formaldehyde do not initiate nor
promote skin tumors. Formaldehyde does not act as a complete tumorigen
when evaluated in the mouse skin painting test.

**870.4300 Carcinogenicity- Rat and Mouse**

Kerns et al. (1983) exposed about 120 animals/sex/species (Fischer 344
rats and B6C3F1 mice) to 0, 2, 5.6 or 14.3 ppm, 6 hours/day, 5 days/week
for 24 months. Five animals per group were sacrificed at 6 and 12 months
and 20 per group were killed at 18 months. At 24 and 27 months the
number sacrificed is unclear. The studies were terminated at 30 months.
From the 12th month on, male and female rats in the highest dose group
(14.3 ppm) showed significantly increased mortality compared with
controls. In the 5.6ppm group, male rats showed a significant increase
in mortality from 17 months on. Female mice showed generally comparable
survival across dose groups, as did male mice, but the male mice as a
whole showed increased mortality because of housing problems. Squamous
cell carcinomas were seen in the nasal cavities of 51/117 male rats and
52/115 female rats at 14.3 ppm (HDT) by experiment\'s end (as many as 35
carcinomas had been identified in males by month 18 based on EPA
analysis notes and Kerns (Chart 8). At 5.6 ppm, 1/119 male rats and
1/116 female rats showed squamous cell carcinomas of the nasal cavity.
No such tumors were seen at 0 or 2 ppm. Polypoid adenomas of the nasal
mucosa were seen in rats at all doses (0 ppm: 1/118 M, 0/114 F; 2 ppm:
4/118 M, 4/118 F; 5.6 ppm: 6/119 M, 0/116 F; 14.3 ppm: 4/117 M, 1/115 F)
in a significant dose-related trend, albeit one that falls off after a
peak. Among the mice, squamous cell carcinomas were seen in two males at
14.3 ppm. No other lesions were noteworthy.

**Non-guideline Carcinogenicity -- Hamster**

Dalbey (1982) examined the effects of inhaled formaldehyde alone for a
lifetime or combined with diethylnitrosamine (DEN) in an
initiation-promotion study design using male Syrian golden hamsters. The
hamsters were housed continuously in stainless steel cages and exposed
in whole body chambers, 5 hours/day, 5 days/week for a lifetime. Two
groups of hamsters were included in the study of inhaled formaldehyde
alone: 132 untreated controls and 88 male hamsters exposed to 10 ppm of
formaldehyde. The study of formaldehyde and DEN interaction involved
five different groups. DEN, administered subcutaneously, was used as the
initiator or primary carcinogen. Formaldehyde was generated by
paraformaldehyde sublimation and monitored by colorimetric analysis.
Fifty animals served as controls; another 50 were exposed to 30 ppm
formaldehyde, 5 hours/day, 1 day/week for life. The third group
consisted of 100 hamsters treated only with DEN (0.5 mg) once per week
for 10 weeks. The fourth group received an exposure to 30 ppm of
formaldehyde 48 hours prior to each weekly injection of DEN for 10 weeks
followed by weekly formaldehyde exposures (5 hours/week) for life. The
fifth group was given weekly 5-hour formaldehyde exposures (30 ppm) for
a lifetime but beginning two weeks after the last DEN injection. In the
formaldehyde-only study, tissues were prepared by hematoxylin and eosin
(H&E) staining and histopathological evaluations were carried out on two
transverse sections of the nasal turbinates (otherwise not specified),
longitudinal sections of larynx and trachea, and all lung lobes cut
along the bronchus prior to embedding. Respiratory tract tissues in the
combination study were stained with Wright's stain and rendered
semitransparent by a clearing technique for subgross evaluation under a
dissecting scope. Areas of dense nuclear staining were scored as tumors.
Nasal turbinates were fixed, decalcified, cut, stained, and cleared for
subgross evaluation. At least 10 lesions observed on the subgross level
in each tissue of each treatment group were examined microscopically.

In the formaldehyde-only (10 ppm) experiment, mortality was reduced in
hamsters (p \< 0.05) relative to unexposed controls. No tumors and
little evidence of toxicity to the nasal epithelium were observed. There
was no increase in rhinitis, and hyperplastic or metaplastic areas were
each observed at an incidence of 5% relative to none in the controls.
While these data are somewhat difficult to interpret given the lack of
information on the location of the nasal sections, they do suggest that
the hamster is less susceptible to inhaled formaldehyde since F344 rats
chronically exposed to ≥10 ppm (Monticello et al., 1996) exhibited an
increase in SCCs, and Wistar rats exposed to 10 ppm for 28 weeks
exhibited significant epithelial disruption (Woutersen et al., 1989).
Differences may be due to dosimetry, as is evident for mice (Chang et
al., 1983), or tissue sensitivity, or both.

In the initiation-promotion protocol with DEN, weekly exposures to
formaldehyde alone (30 ppm once per week) did not influence mortality.
Treatment with DEN alone significantly (p \< 0.05) increased mortality
above that of untreated controls, and mortality was further elevated (p
\< 0.05) in the two groups exposed to both DEN and formaldehyde relative
to DEN alone. Actual group size was 27 for concurrent DEN and
formaldehyde treatment and 23 for formaldehyde given after DEN because
of unplanned mortality resulting from an exposure accident at 48 weeks.
No tumors were observed in untreated animals or those receiving only
formaldehyde. DEN treatment alone resulted in a high incidence (77%) of
tumors. All tumors observed were classified as adenomas. Lifetime
exposure of animals treated with DEN and formaldehyde did not increase
the number of TBA above those given DEN only. The number of tumors per
tumor-bearing animal (TBA) was significant only in the group given
formaldehyde prior to each DEN injection and only in the trachea and not
in larynx or lung. An adjustment of the tumor incidence for age at death
may have increased the statistical significance further. The author
concluded that the relation of the time of exposures to formaldehyde to
the DEN appeared to be significant, noting that the formaldehyde
exposure resulted in an increase only when administered 48 hours prior
to each injection. These findings may be due to a cytotoxic effect of
formaldehyde on cell proliferation as later shown by Monticello et al.
(1996) for rats.

**870.4300** **Combined Chronic Toxicity/Carcinogenicity -- Rat and
Mouse**

In a combined chronic toxicity/carcinogenicity study (MRID 00143289),
Rats (Fischer 344) and Mice (B6C3F~1~) were administered 0, 2.0, 5.6, or
14.3 ppm (0, 2.5, 6.9, or 18 mg/m^3^) formaldehyde via inhalation, 6
hrs/day, 5 days/week, for up to 24 months.

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

In male mice, there were no differences in survival. The number of male
mice surviving a minimum of 18 months were 41, 33, 32, and 25 for the 0,
2.5, 6.9, and 18 mg/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^.

> **Epidemiology Studies**

The follow-up study by Hauptmann et al. (2003, 2004) of the National
Cancer Institute (NCI) retrospective cohort mortality study of U.S.
workers involved in the production or use of formaldehyde represents the
best available data set for quantitative cancer risk assessments of
lymphohematopoietic cancers and nasopharyngeal tumors based on human
data. The NCI study is a large epidemiology study, and it provides
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. Significant increases in relative risk for
lymphohematopoietic cancer were observed primarily for myeloid leukemia
and Hodgkin's disease and for the peak exposure and average intensity
exposure metrics. For the nasopharyngeal cancers, significant trends
were observed for the cumulative and peak exposure metrics.

With respect to the subtypes of lymphohematopoietic malignancy, the
strongest exposure-response relationships were observed for Hodgkin's
disease and myeloid leukemia for both the peak exposure and average
intensity exposure metrics. The (all) lymphohematopoietic malignancies
category also showed a highly significant trend for the peak exposure
metric and a significant trend with the average intensity metric, and
this was the category selected for the cancer risk analyses presented
here. While other lymphohematopoietic cancer subtypes did not exhibit
statistically significant increases, many did suggest increases in
relative risk with formaldehyde exposure, and the subtype analyses were
generally based on small numbers of cases (i.e., lower statistical
power). Furthermore, as noted by the NCI investigators, "\[a\]lthough
the accuracy of death certificates for lymphohematopoietic malignancies
is generally high, classification of subtypes of leukemia and lymphoma
from death certificates is less accurate than from hospital records."
Finally, the all lymphohematopoietic cancer category contains the most
data, and the results are more stable.

> **4.8 Mutagenicity**

[Adequacy of database for Mutagenicity Toxicity]{.underline}: The
database for mutagenicity of formaldehyde is considered incomplete with
the lack of a bone marrow chromosome

aberration test in the mouse.

The mutagenicity data for Formaldehyde is summarized below in Table 3.

+--------------+-------------------+--------------+------------------+
| **Table 3.   |                   |              |                  |
| Mutagenicity |                   |              |                  |
| data for     |                   |              |                  |
| Fo           |                   |              |                  |
| rmaldehyde** |                   |              |                  |
+==============+===================+==============+==================+
| **Guideline  | **MRID No./**     | **Dosing and | **Results**      |
| No./**       |                   | Animal       |                  |
|              | **Reference       | I            |                  |
| **Study      | Information/**    | nformation** |                  |
| Type**       |                   |              |                  |
|              | **Study           |              |                  |
|              | Classification**  |              |                  |
+--------------+-------------------+--------------+------------------+
| **Mu         |                   |              |                  |
| tagenicity** |                   |              |                  |
+--------------+-------------------+--------------+------------------+
| 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          |              |                  |
|              | Sal               | TA-100,      |                  |
|              | monella/Microsome | TA-1535      |                  |
|              | Plate Test: LBI   |              |                  |
|              | Project No.       | TA-I 537 and |                  |
|              | 20838. Final      | TA-1538.     |                  |
|              | rept.             | S            |                  |
|              | (Unpublished      | accharamyces |                  |
|              | study received    | indicator    |                  |
|              | May 9, 1983 under | organisms,   |                  |
|              | 38906-5; prepared | strain 04.   |                  |
|              | by Litton         |              |                  |
|              | 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.;       | MA #T1804)   | caused did cause |
| mutation     | Burke, P.; et al. | tested at    | a positive       |
| test         | (1982).           | co           | response         |
|              | Salmonella/       | ncentrations | (3.2-fold        |
|              |                   | of 3.0,      | increase) on     |
|              | Ma                | 15.0, 75.0,  | tester strain    |
|              | mmalian-microsome | 150, or 300  | TA98 without     |
|              | Preincubation     | µg/plate.    | metabolic        |
|              | Mutagenicity      |              | activation. A    |
|              | Assay (Ames       | Tester       | 1.9-fold         |
|              | Test): Test       | strains      | increase was     |
|              | Article 447:34-3: | TA98, TA100, | observed on TA98 |
|              | Study No.         | TA1535,      | with metabolic   |
|              | T1804.502.        | TA1357,      | activation.      |
|              | (Unpublished      | TA1358 ±     | Also, increases  |
|              | study received    | metabolic    | of 2.2-fold and  |
|              | May 9, 1983 under | activation   | 1.7-fold were    |
|              | 38906-5; prepared | with araclor | observed on      |
|              | by                | induced rat  | tester strain    |
|              | Microbiological   | liver        | TA100 with and   |
|              | Assoc., submitted | microsomes.  | without          |
|              | by Glyco, Inc.,   |              | activation,      |
|              | Greenwich, CT;    |              | respectively.    |
|              | CDL:250313-B).    |              |                  |
|              |                   |              |                  |
|              | **Acceptable**    |              |                  |
+--------------+-------------------+--------------+------------------+
| 870.5100     | O\'DONOVAN, MR    | 0-200        | Pre-incubation   |
|              | AND 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         | i            |                  |
|              | STRAINS;          | ncorporation | Standard         |
|              | MUTAGENESIS       | assays       | pla              |
|              | 8(6):577-581,     |              | te-incorporation |
|              | 1993              | S.           | assays:          |
|              |                   | typhimurium  |                  |
|              | (NCEA)            | Strains      | Consistent       |
|              |                   | TA1535,      | mutagenicity was |
|              | **Open            | TA1537,      | seen only for    |
|              | Literature**      | TA1538,      | TA100 and        |
|              |                   | TA98, TA100, | WP2uvrA          |
|              |                   | and TA102    | (pKM101).        |
|              |                   | and E.coli   |                  |
|              |                   | Strains      | No evidence of   |
|              |                   | WP2(pKM101)  | mutagenicity was |
|              |                   | and          | seen for TA1535, |
|              |                   | WP2          | TA1537, or       |
|              |                   | uvrA(pKM101) | TA1538 using     |
|              |                   |              | either method of |
|              |                   | Purity: 37%  | exposure.        |
+--------------+-------------------+--------------+------------------+
| 870.5100     | Schmid, E., W.    | The tests    | Plate Assay:     |
|              | Goggelmann; and   | were carried | weak positive    |
| Bacterial    | M. Bauchinger.    | out using    | response         |
| reverse      | (1986)            | the plate    |                  |
| mutation     | For               | i            | Pre-Incubation   |
| test         | maldehyde-induced | ncorporation | Method: Without  |
|              | Cytotoxic,        | assay and    | S9 mix,          |
|              | Genotoxic, and    | the          | a1.6-fold        |
|              | Mutagenic         | pr           | increase of      |
|              | Response in Human | e-incubation | revertant        |
|              | Lymphocytes and   | method +/-   | numbers over     |
|              | Salmonella        | S9           | controls was     |
|              | typhimurium.      | activation   | induced. With S9 |
|              | Mutagenesis vol.  | at doses of  | mix, a 2.7-fold  |
|              | 1 no. 6 p.        | 0-1.5mM and  | increase of      |
|              | 427-431. (NCEA)   | 0-0.3mM      | revertant        |
|              |                   | f            | numbers over     |
|              | **Open            | ormaldehyde, | controls was     |
|              | Literature**      | 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     | []{.mark}         | The capacity | Both toxicity    |
|              |                   | of           | and mutagenicity |
| Bacterial    | Temcharoen, P;    | formaldehyde | were obtained at |
| reverse      | Thilly, WG.       | to induce    | formaldehyde     |
| mutation     | (1983) Toxic and  | forward      | concentrations   |
| test         | mutagenic effects | mutations to | of 0.17 mM in    |
|              | of formaldehyde   | 8-azaguanine | the absence of   |
|              | in Salmonella     | resistance   | S9 and 0.33 mM   |
|              | typhimurium.      | in was       | in the presence  |
|              | Mutat Res         | examined.    | of S9. The       |
|              | 119:89-93. (NCEA) | Formaldehyde | authors noted    |
|              |                   | co           | that, while the  |
|              | **Open            | ncentrations | S9 might be      |
|              | Literature**      | 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           | trials       |                  |
|              | Laboratory Report |              |                  |
|              | No. 581-80).      | Mouse        |                  |
|              |                   | Lymphoma     |                  |
|              | **Open            | L5178Y Cell  |                  |
|              | Literature**      |              |                  |
|              |                   | Purity: 37%  |                  |
+--------------+-------------------+--------------+------------------+
| 870.5275     | Valencia, R.,     | Doses of     | **Positive**     |
|              | J.M. Mason, and   | 2,600 and    |                  |
| Sex-linked   | S. Zimmering.     | 1,100 ppm    |                  |
| recessive    | (1989) Chemical   |              |                  |
| lethal test  | Mutagenesis       | D.           |                  |
| in           | Testing in        | melanogaster |                  |
| Drosophila   | Drosophila. VI.   | (Canton-S M  |                  |
| melanogaster | Interlaboratory   | and Basc F)  |                  |
|              | Comparison of     |              |                  |
|              | Mutagenicity      | Purity: 37%  |                  |
|              | Tests 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.;      | was tested   | caused a         |
| chromosome   | Pant, 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      | ovary cells  | and without S-9  |
|              | study received    | (cell        | activation.      |
|              | May 9, 1983 under | repository   |                  |
|              | 38906-5; prepared | number CCL,  |                  |
|              | by                | 61)          |                  |
|              | Microbiological   |              |                  |
|              | Assoc., submitted | Purity: 37%  |                  |
|              | by Glyco, Inc.,   | Formalin     |                  |
|              | Greenwich, CT;    |              |                  |
|              | CDL:250313-M)     |              |                  |
|              |                   |              |                  |
|              | **Acceptable**    |              |                  |
+--------------+-------------------+--------------+------------------+
| 870.5375     | []{.mark}         | In Vitro     | **In Vitro:      |
|              |                   |              | Positive**       |
| In Vitro     | Natarajan, A.T.   | CHO cells    |                  |
| mammalian    | et al. (1983)     | exposed to   | Frequencies of   |
| chromosome   | Evaluation of the | 0, 0.003,    | chromosomal      |
| aberration   | mutagenicity of   | 0.006,       | aberrations and  |
| test         | formaldehyde in   | 0.012, or    | SCEs increased   |
|              | mammalian         | 0.024 uL/mL  | with increasing  |
|              | cytogenics assays | para         | dose. All        |
|              | in vivo and       | formaldehyde | classes of       |
|              | vitro. Mutation   |              | aberration, i.e. |
|              | Research 122:     | In Vivo      | gaps, breaks,    |
|              | 355-360. (NCEA)   | Mouse        | and exchanges,   |
|              |                   |              | were induced by  |
|              | **Open            | 0.4 mL       | formaldehyde.    |
|              | Literature**      | 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     | Font              | Mice         | **Negative**     |
|              | ignie-Houbrechts, | received an  |                  |
| Mammalian    | N. (1981) Genetic | i.p.         | No chromosomal   |
| sp           | Effects of        | injection of | lesions were     |
| ermatogonial | Formaldehyde in   | 50 mg/kg     | revealed         |
| chromosomal  | the Mouse.        | formaldehyde |                  |
| aberration   | Mutation          |              |                  |
| test         | Research, v. 88,  | M Q Strain   |                  |
|              | p. 109-114.       | Mouse (200   |                  |
|              | (NCEA)            | sp           |                  |
|              |                   | ermatocytes/ |                  |
|              | **Open            | animal)      |                  |
|              | Literature**      |              |                  |
|              |                   | Purity: 35%  |                  |
+--------------+-------------------+--------------+------------------+
| 870.5450     | Font              | Mice         | Embryonic death  |
|              | ignie-Houbrechts, | received an  | or pre-post      |
| Rodent       | N. (1981) Genetic | i.p.         | implantation     |
| dominant     | Effects of        | injection of | death at 1 and 3 |
| lethal assay | Formaldehyde in   | 50 mg/kg     | week periods     |
|              | the Mouse.        | formaldehyde |                  |
|              | Mutation          | and 10 males |                  |
|              | Research, v. 88,  | were caged   |                  |
|              | p. 109-114. (as   | with 2       |                  |
|              | cited in Ma and   | virgin       |                  |
|              | Harris) (NCEA)    | females each |                  |
|              |                   | for one      |                  |
|              | **Open            | week. The    |                  |
|              | Literature**      | 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     | int          |                  |
| Rodent       | Head              | erperitonial | The frequency of |
| dominant     | Abnormalities and | injections   | dominant lethal  |
| lethal assay | Dominant Lethal   | of 0.125,    | mutations in     |
|              | Effects of        | 0.250, and   | female rats      |
|              | Formaldehyde in   | 0.6 mg/kg    | sired by males   |
|              | Albino Rats."     | f            | exposed to       |
|              | Mutation Research | ormaldehyde. | formaldehyde was |
|              | 389: 141-148.     | Males were   | significantly    |
|              |                   | caged with 2 | higher than the  |
|              | **Open            | untreated    | control group.   |
|              | Literature**      | 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 in | Unscheduled DNA   | at           | significant      |
| mammalian    | Synthesis in Rat  | co           | increase in UDS  |
| cells in     | Hepatocytes: Test | ncentrations | in rat           |
| culture      | Article 447:34-1: | of 0.0005,   | hepatocytes.     |
|              | Study No.         | 0.001,       |                  |
|              | T1802.380002.     | 0.005, 0.01, |                  |
|              | (Un- published    | 0.02, or     |                  |
|              | study received    | 0.04 µL/mL.  |                  |
|              | May 9, 1983 under |              |                  |
|              | 38906-5; prepared | Primary rat  |                  |
|              | by                | liver        |                  |
|              | Microbiological   | hepatocytes  |                  |
|              | Assoc., submitted | --           |                  |
|              | by Glyco, Inc.,   | Sp           |                  |
|              | Greenwich, CT;    | rague-Dawley |                  |
|              | CDL:250313-N)     | rats, 2.5 x  |                  |
|              |                   | 10^5^        |                  |
|              | **Acceptable**    | HPC/plate    |                  |
|              |                   |              |                  |
|              |                   | Purity: 37%  |                  |
|              |                   | a.i.         |                  |
+--------------+-------------------+--------------+------------------+
| 870.5900     | A. Basler, W. v.  | []{.mark}    | There was a      |
|              | d. Hude, and M.   |              | three- to        |
| *In Vitro*   | S                 | The test     | four-fold        |
| Sister       | cheutwinkel-Reich | compound was | increase in the  |
| Chromatid    | (1985)            | added to     | SCE frequency at |
| Exchange     | "For              | cell         | non-toxic doses. |
| Assay        | maldehyde-Induced | cultures 18  | However, in the  |
|              | Sister Chromatid  | hours after  | presence of an   |
|              | Exchanges in      | seeding 5 x  | exogenous        |
|              | vitro and the     | 10^5^ cells  | metabolizing     |
|              | Influence of the  | per 25 cm^2^ | system, the      |
|              | Exogenous         | flask. The   | number of        |
|              | Metabolizing      | exposure     | form             |
|              | Systems S9 Mix    | time was 1,  | aldehyde-induced |
|              | and Primary Rat   | 2, 3, or 28  | SCE's decreased. |
|              | Hepatocytes."     | hours. In    | S9 mix as well   |
|              | Arch Toxicol 58:  | the          | as hepatocytes   |
|              | 10-13.            | experiments  | reduced the SCE  |
|              |                   | with         | frequency to     |
|              | **Open            | short-term   | nearly that of   |
|              | Literature**      | exposure     | the control      |
|              |                   | (1-3 hours), | range. It could  |
|              | []{.mark}         | the medium   | be demonstrated  |
|              |                   | was removed  | that the         |
|              |                   | after this   | reduction was    |
|              |                   | treatment.   | not due to an    |
|              |                   | The cells    | unspecific       |
|              |                   | were         | binding of       |
|              |                   | restored in  | formaldehyde to  |
|              |                   | medium       | macromolecules   |
|              |                   | supplemented | of the added S9  |
|              |                   | with         | mix. The         |
|              |                   | 5-bromo-2-   | decrease in      |
|              |                   | deoxyuridine | genotoxic        |
|              |                   | (BrdU). The  | effects, due to  |
|              |                   | cells were   | rapid            |
|              |                   | cultured in  | metabolisation   |
|              |                   | the presence | of formaldehyde  |
|              |                   | of BrdU      | in vitro and un  |
|              |                   | (10^-5^ M)   | vivo, explains   |
|              |                   | for 28 h,    | the differences  |
|              |                   | with         | between results  |
|              |                   | colcemide    | obtained in the  |
|              |                   | (0.1 µg/ml)  | in vitro         |
|              |                   | for the last | experiments --   |
|              |                   | 4 h. In the  | performed        |
|              |                   | experiments  | without          |
|              |                   | with         | metabolizing     |
|              |                   | long-term    | systems -- and   |
|              |                   | exposure,    | in vivo results. |
|              |                   | the cells    |                  |
|              |                   | were         |                  |
|              |                   | cultured in  |                  |
|              |                   | the presence |                  |
|              |                   | of BrdU and  |                  |
|              |                   | the test     |                  |
|              |                   | compounds    |                  |
|              |                   | for 28 hr.   |                  |
|              |                   | In tests     |                  |
|              |                   | with S9 mix, |                  |
|              |                   | the cells    |                  |
|              |                   | were         |                  |
|              |                   | incubated    |                  |
|              |                   | with 0.5 ml  |                  |
|              |                   | S9 mix per   |                  |
|              |                   | 25 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)            | 15 ppm (0.6, | chromosome       |
| Chromatid    | Cytogenetic       | 7.4, 18.5    | aberrations at   |
| Exchange     | analysis of       | mg/m^3^)     | any dose level.  |
| Assay        | lymphocytes from  | formaldehyde |                  |
|              | rats following    | by           |                  |
|              | formaldehyde      | inhalation   |                  |
|              | inhalation.       | for 6        |                  |
|              | Toxicol Lett      | hours/day    |                  |
|              | 21:241-246.       | for 5 days.  |                  |
|              |                   | Blood was    |                  |
|              | **Open            | obtained by  |                  |
|              | Literature**      | 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     | 50, 125, or  |                  |
| lymphoblasts | T.R. Skopek       | 150uM        | The 15, 30, and  |
|              | (1987)            |              | 50 uM treatments |
|              | Formaldehyde      | Human        | resulted in no   |
|              | mutagenesis and   | Lymphoblasts | significant      |
|              | formation of      | (4x 10\^5    | difference in    |
|              | DNA-protein       | cells/mL)    | growth rate      |
|              | crosslinks in     |              | compared to      |
|              | human             | Formaldehyde | control values;  |
|              | lymphoblasts in   | (37% w/w     | the 125 uM       |
|              | vitro. Mutation   | 10-15%       | and150 uM        |
|              | Research 176:     | methanol)    | treatments       |
|              | 147-155.          |              | resulted in      |
|              |                   |              | approximately    |
|              | **Open            |              | 30% and 20%      |
|              | Literature**      |              | 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  |
| lymphoblasts | Crosby, RM; et    | followed up  | that the point   |
|              | al. (1989)        | the findings | mutations fall   |
|              | For               | of Crosby et | into four        |
|              | maldehyde-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;       | analysis of  | transversions,   |
|              | Jones, S; Green,  | formalde     | including three  |
|              | T. (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  |
|              | form              | L5178Y tk+/- | in the absence   |
|              | aldehyde-mediated | cells        | and presence of  |
|              | mutagenicity      |              | rat liver S9     |
|              | using the mouse   | Purity: 37%  | (higher          |
|              | lymphoma L5178Y   | (w/w)        | concentrations   |
|              | TK positive       | aqueous      | required for     |
|              | negative assay    | solution     | effect with S9). |
|              | supplemented with | (formalin)   | Both toxicity    |
|              | formaldehyde      |              | and mutagenicity |
|              | dehydrogenase. In |              | were abolished   |
|              | Vitro Toxicology  |              | when             |
|              | 4:121-132.        |              | formaldehyde     |
|              |                   |              | dehydrogenase    |
|              | **Open            |              | was incorporated |
|              | Literature**      |              | in the exposure  |
|              |                   |              | medium.          |
+--------------+-------------------+--------------+------------------+

**4.9 Neurotoxicity**

[Adequacy of database for Neurotoxicity]{.underline}: The database for
neurotoxicity consists of four open literature studies.

**870.6200 Neurotoxicity Screening Battery -- Rat**

Malek et al. (2003a) examined open field behavior of rats after acute
formaldehyde exposures. Male and female LEW.1K rats (15/sex/group) were
exposed to 0, 1.0, 2.5, or 5.0 ppm (0, 1.23, 3.08, or 6.15 mg/m3)
formaldehyde for 2 hours. Formaldehyde was vaporized from aqueous
solutions directly below the exposure chamber. Formaldehyde levels were
checked 16 times throughout the 2-hour exposure periods. Mean
formaldehyde levels of 1.01 ± 0.29 ppm, 2.51 ppm (standard deviation is
missing) and 5.04 ± 0.27 ppm were achieved. Locomotor activity was
assessed for 1 hour in an open field 2 and 24 hours after termination of
formaldehyde exposure using an automated device to count the number of
squares crossed. Other behaviors were noted, including grooming (face
cleaning, fur licking, and scratching), rearing, sniffing (air and
floor), wall climbing, and defecation.

The authors reported no signs of irritation or changes in activity or
food or water intake during exposure (Malek et al., 2003a). In general,
sniffing was increased after formaldehyde exposure and movement was
decreased (crossed quadrants and climbing) in both male and female rats
(p\<0.05). Significant reductions in horizontal movements (crossed
quadrants) were observed at all dose levels and were characterized by a
U-shaped dose response. The lowest dose tested (1 ppm) demonstrated
higher level of activity suppression than the two higher doses, but all
groups were still suppressed relative to controls. Although female rats
displayed a greater level of activity overall, a similar U-shaped
dose-response pattern was also observed.

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

**The neurotoxicity LOAEL was established to be 1.0 ppm, 2 hours**

A follow-up study by Malek et al. (2003b) further expanded the
dose-response analysis for acute formaldehyde exposure. As described
above, male and female LEW.1K rats (10 per group) were exposed at 0,
0.1, 0.5, or 5.0 ppm (0, 0.123, 0.615, or 6.15 mg/m3) formaldehyde for 2
hours. Formaldehyde levels were checked 16 times throughout the 2-hour
exposure periods and mean values were found to be 0.13 ± 0.04, 0.48 ±
0.05, and 5.18 ± 0.66 ppm. Open field behavior tests were conducted on
each animal 2 hours after formaldehyde exposure. 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.

**The neurotoxicity LOAEL (Males) was established to be 0.1 ppm, 2
hours**

**870.6500 Scheduled Control Operant Behavior -- Rat**

Pitten et al. (2000) evaluated the effects of very brief formaldehyde
exposures (10 minutes) but prolonged duration (90 days) on previously
learned performance in a land version of the labyrinth maze. Adult male
and female Wistar rats were acclimated to the task for 14 days, 2
trials/day. Animals were required to make a series of five consecutive
turns from the entrance of the maze to retrieve a piece of cheese placed
in the goal box at the opposite end. Animals were guided by the
experimenter through the maze during this acclimation phase until all
subjects were able to retrieve the food without aid. A pretraining phase
followed in which performance was assessed once daily for 11 days, and
the latency to complete the maze, as well as the number of errors
committed when traversing from the entrance to the goal box, were
recorded. The maze was wiped clean between subjects to remove urine,
boli and olfactory stimuli from the previous subject. Animals were then
assigned to one of three dose groups (five to eight/sex/group) such that
task performance was equivalent across groups prior to commencement of
formaldehyde exposures. Animals were exposed to 0 ppm, 2.6 ppm (0.25%
formaldehyde solution to yield 3.06 ± 0.77 mg/m3), or 4.6 ppm (0.70%
formaldehyde solution to yield 5.55 ± 1.27 mg/m3) formaldehyde, 10
minutes/day, 7 days/week for 90 days. Animals were assessed for
performance in the maze every seventh day, at least 22 hours after the
exposure on the previous day. At the end of the 90-day exposure period,
monitoring of maze performance continued once every 10 days for an
additional 40 days. All rats were sacrificed at the end of the
post-exposure trials and tissue sections were prepared for histological
examination by light microscopy, including liver, trachea, lung, kidney,
heart, spleen, pancreas, testicle, and brain. No changes in food or
water consumption weight gain or in histological samples of lung and
liver obtained at the termination of the experiment were observed.

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

**The neurotoxicity LOAEL was established to be 2.6 ppm, 10 min/90
days.**

**Non-Guideline Neurotoxicity**

In a neurotoxicity study conducted by Boja (1985), male 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 6.20 mg/m^3^ formaldehyde resulted in statistically
significant decreased motor activity within 15 minutes. At the beginning
of day 2, all of the rats exposed to formaldehyde on day 1 displayed
lower activity levels. Similar effects on motor activity were seen at
the 12.39 mg/m^3^ formaldehyde exposure level, whereas effects seen
after 24.79 mg/m^3^ exposure were reported to be "not readily
interpretable" and were not shown. 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.

**4.10 Metabolism and Pharmacokinetics**

[Adequacy of database for Metabolism and Pharmacokinetics]{.underline}:
The database for metabolism of formaldehyde is considered complete with
one submitted and two open literature studies in the rat.

**870.7485 General Metabolism**

In a metabolism study conducted by Casanova et al. (1989), rats
(4/group) were exposed to formaldehyde (nose-only exposure) at
concentrations of 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.

DNA-protein crosslinking occurred at all concentrations. The formation
of crosslinks was interpreted in terms of a nonlinear pharmacokinetic
model incorporating oxidation of inhaled formaldehyde as a defense
mechanism. The slope of the fitted concentration-response curve at 12
mg/m^3^ is7.3-fold greater than at 0.37 mg/m^3^, and the detoxification
pathway is half-saturated at an airborne concentration of 3.2 mg/m^3^.

**870.7485 General Metabolism**

In a metabolism study (Casanova-Schmitz et al., 1984), 14C and
3H-formaldehyde was administered at doses of 0, 0.3, 2, 6, 10, or 15 ppm
(0, 0.37, 2.5, 7.4, 12, or 19 mg/m^3^) for 6 hours.

The major route of nucleic acid labeling at all concentrations and in
all tissues was metabolic incorporation; protein labeling in the
respiratory mucosa was mainly due to covalent binding at the higher
formaldehyde concentration. Incorporation of 14C- formaldehyde into DNA
in the respiratory mucosa was maximal at 7.4 mg/m^3^ but decreased at
higher concentrations, whereas labeling of DNA in the olfactory mucosa
and bone marrow increased monotonically with concentration. Evidence for
covalent binding of formaldehyde to respiratory mucosal DNA was obtained
at formaldehyde concentrations equal to or greater than 2.5 mg/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.

**4.11 Special Studies**

The special studies data for formaldehyde is summarized in Table 4
below:

+--------------------+-------------------------+-----------------------+
| **Table 4. Special |                         |                       |
| studies data for   |                         |                       |
| Formaldehyde**     |                         |                       |
+====================+=========================+=======================+
| **Guideline        | **MRID Number (Year)/** | **Results**           |
| Number/**          |                         |                       |
|                    | **Citation/**           |                       |
| **Study Type/**    | **Classification/       |                       |
|                    | Doses**                 |                       |
| **Test Substance   |                         |                       |
| (% a.i.)**         |                         |                       |
+--------------------+-------------------------+-----------------------+
| Modeling           | Conolly, R.B., et al.   | The analysis          |
|                    | 2003. Biologically      | suggested evidence    |
|                    | Motivated Computational | of: 1) a              |
|                    | Modeling of             | cytol                 |
|                    | Formaldehyde            | ethality-regenerative |
|                    |                         | cellular              |
|                    | Carcinogenicity in the  | proliferation (CRCP)  |
|                    | F344 Rat. Toxicol. Sci. | mechanism with little |
|                    | 75: 432--447.           | or no involvement of  |
|                    |                         | direct mutagenesis;   |
|                    | **Open Literature**     | and 2) a J-shaped     |
|                    |                         | dose-response         |
|                    | 3-D F344 Rat Model      | relationship between  |
|                    |                         | formaldehyde and      |
|                    | Biologically based      | squamous cell         |
|                    | quantitative modeling   | carcinoma.            |
|                    | 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.            |                       |
+--------------------+-------------------------+-----------------------+
| Sensitization      | []{.mark}               | []{.mark}             |
|                    |                         |                       |
|                    | Ohtsuka, R; Shuto, Y;   | Although no pulmonary |
|                    | Fujie, H; et al. (1997) | measurements were     |
|                    | Response of respiratory | made, the authors     |
|                    | epithelium of BN and    | observed fewer        |
|                    | F344 rats to            | clinical signs of     |
|                    | formaldehyde            | respiratory           |
|                    | inhalation. Exp Anim    | irritation in the BN  |
|                    | 46:279-286. (NCEA)      | rats compared to F344 |
|                    |                         | rats, such as         |
|                    | Ohtsuka, R; Shutoh, Y;  | abnormal respiration  |
|                    | Fujie, H; et al. (2003) | (three versus five)   |
|                    | Rat strain difference   | and nasal discharge   |
|                    | in histology and        | (three versus five).  |
|                    | expression of Th1- and  | Formaldehyde-treated  |
|                    | Th2-related cytokines   | F344 rats showed less |
|                    | in nasal mucosa after   | body weight gain over |
|                    | short-term formaldehyde | the 2-week treatment, |
|                    | inhalation. Exp Toxicol | resulting in lower    |
|                    | Pathol 54:287-291.      | body weight at week 1 |
|                    |                         | and week 2 than F344  |
|                    | # Open Literature       | controls (p\<0.05 and |
|                    |                         | 0.01). BN rats were   |
|                    | []{.mark}               | more resistant to     |
|                    |                         | epithelial cell       |
|                    | 18 F344 and 18 Brown    | damage than F344      |
|                    | Norway (BN) Rats        | rats, exhibiting      |
|                    |                         | milder lesions that   |
|                    | []{.mark}               | impacted a smaller    |
|                    |                         | portion of the URT.   |
|                    | Rats were exposed to    | Squamous metaplasias  |
|                    | formaldehyde aerosol    | were present in the   |
|                    | for 3 hours/day, 5      | respiratory           |
|                    | days/week for 2 weeks.  | epithelium (Levels 1  |
|                    | The aerosol was         | and 2) in both        |
|                    | generated from a 1%     | strains in            |
|                    | formaldehyde solution   | formaldehyde-treated  |
|                    | by a two-fluid atomizer | rats. However, a      |
|                    | and formaldehyde level  | distinct keratinized  |
|                    | maintained at 2 mg (1%  | layer was noted in    |
|                    | sol.)/L (approximately  | Level 1 epithelium of |
|                    | 16 ppm or 20 mg/m^3^),  | F344 rats, and the    |
|                    | by adjusting the flow   | extent of lesions in  |
|                    | rate for formaldehyde   | Level 2 respiratory   |
|                    | solution to the         | epithelium was much   |
|                    | atomizer.               | greater than that     |
|                    |                         | seen in BN rats.      |
|                    | []{.mark}               | Additionally, the     |
|                    |                         | olfactory epithelium  |
|                    |                         | (Level 2) in          |
|                    |                         | formaldehyde-exposed  |
|                    |                         | F344 rats exhibited   |
|                    |                         | degeneration,         |
|                    |                         | necrosis, and         |
|                    |                         | desquamation not seen |
|                    |                         | in BN rats. Mild      |
|                    |                         | squamous metaplasia   |
|                    |                         | was noted in Level 3  |
|                    |                         | of the respiratory    |
|                    |                         | epithelium in the     |
|                    |                         | treated F344 rats but |
|                    |                         | not the BN rats. The  |
|                    |                         | authors note that     |
|                    |                         | their earlier         |
|                    |                         | research indicated    |
|                    |                         | the BN rats have      |
|                    |                         | well-developed        |
|                    |                         | submucosal glands and |
|                    |                         | that greater mucus    |
|                    |                         | flow may be partly    |
|                    |                         | responsible for the   |
|                    |                         | greater resistance of |
|                    |                         | BN rats to the        |
|                    |                         | histological signs of |
|                    |                         | formaldehyde          |
|                    |                         | toxicity.             |
|                    |                         |                       |
|                    |                         | In a subsequent study |
|                    |                         | in the same           |
|                    |                         | laboratory, Ohtsuka   |
|                    |                         | et al. (2003)         |
|                    |                         | compared cytokine     |
|                    |                         | profiles in the nasal |
|                    |                         | mucosa of             |
|                    |                         | formaldehyde-treated  |
|                    |                         | F344 and BN rats.     |
|                    |                         | Formaldehyde aerosol  |
|                    |                         | was generated as      |
|                    |                         | above and rats (nine  |
|                    |                         | per group) were       |
|                    |                         | exposed 3 hours/day   |
|                    |                         | for 5 days to         |
|                    |                         | approximately 16 ppm  |
|                    |                         | of formaldehyde (20   |
|                    |                         | mg/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.     |
+--------------------+-------------------------+-----------------------+
| Sensitization      | []{.mark}               | Methacholine          |
|                    |                         | challenge increased   |
| Purity: 37%        | Biagini, RE; Moorman,   | pulmonary flow        |
| formalin           | WJ; Knecht, EA; et al.  | resistance at         |
|                    | (1989) Acute airway     | increasing levels of  |
|                    | narrowing in monkeys    | methacholine (0.125,  |
|                    | from challenge with 2.5 | 0.5, 2.0, and 8.0     |
|                    | ppm formaldehyde        | mg/mL) to 196 ± 16,   |
|                    | generated from          | 285 ± 57, 317 ± 64,   |
|                    | formalin. Arch Environ  | and 461 ± 120 % of    |
|                    | Health 44:12-17. (NCEA) | baseline levels       |
|                    |                         | respectively.         |
|                    | **Open Literature**     | Similarly,            |
|                    |                         | formaldehyde exposure |
|                    | 9 Cynomolgus Monkeys    | increased pulmonary   |
|                    | known to be             | flow resistance from  |
|                    | hyperreactive to        | 11.3 ± 1.4 cm H2O     |
|                    | methacholine            | prior to formaldehyde |
|                    | (acetyl-β-methacholine  | exposure, to 16.1 ±   |
|                    | chloride)               | 2.1, 16.9 ± 2.8, and  |
|                    |                         | 20.0 ± 3.4 cm H2O, at |
|                    | The effect of a single  | 2, 5, and 10 minutes  |
|                    | pulmonary exposure on   | after formaldehyde    |
|                    | pulmonary mechanics     | exposure (with 142,   |
|                    | including bronchial     | 150, and 177% change, |
|                    | constriction (BC) was   | respectively).        |
|                    | evaluated. Each monkey  | Although bronchial    |
|                    | was exposed separately  | constriction, seen as |
|                    | to methacholine and     | increased pulmonary   |
|                    | formaldehyde in order   | flow resistance, was  |
|                    | to compare their        | increased by both     |
|                    | formaldehyde response   | methacholine and      |
|                    | to an agent known to    | formaldehyde, there   |
|                    | trigger BC. Monkeys     | was not a correlation |
|                    | were exposed to         | between methacholine  |
|                    | increasing levels of    | responsiveness and    |
|                    | methacholine for 10     | the magnitude of      |
|                    | minutes (0, 0.125, 0.5, | effect after          |
|                    | 2.0, and 8.0 mg/mL) as  | formaldehyde exposure |
|                    | an aerosol (0.065       | (p\>0.1). Therefore   |
|                    | mL/min with a mean      | although formaldehyde |
|                    | aerodynamic diameter of | exposure stimulated   |
|                    | 1.0-1.5 μm). After a    | BC similarly to a     |
|                    | 2-week recovery period, | known direct          |
|                    | pulmonary mechanics     | stimulating agent,    |
|                    | were measured before    | formaldehyde may not  |
|                    | and after a 10-minute   | work through the same |
|                    | exposure to 2.5 ppm     | site of action as     |
|                    | formaldehyde (2, 5, and | methacholine.         |
|                    | 10 minutes              |                       |
|                    | post-exposure).         |                       |
+--------------------+-------------------------+-----------------------+
| Sensitization      | []{.mark}               | In nonimmunized mice, |
|                    |                         | spleen weights were   |
|                    | Fujimaki, H; Kurokawa,  | reduced by            |
|                    | Y; Kunugita, N; et al.  | formaldehyde exposure |
|                    | (2004) Differential     | from 152 mg in        |
|                    | immunogenic and         | control to 128, 118,  |
|                    | neurogenic inflammatory | and 121 mg in mice    |
|                    | responses in an         | exposed to 0.08,      |
|                    | allergic mouse model    | 0.40, and 1.8 ppm     |
|                    | exposed to low levels   | formaldehyde,         |
|                    | of formaldehyde.        | respectively.         |
|                    | Toxicology 197:1-13.    | However, spleen       |
|                    | (NCEA)                  | weights were          |
|                    |                         | unchanged by          |
|                    | **Open Literature**     | formaldehyde exposure |
|                    |                         | in OVA-immunized      |
|                    | Mice were exposed to 0, | mice. In immunized    |
|                    | 0.082, 0.393, or 1.87   | mice exposed to 1.8   |
|                    | ppm formaldehyde (0,    | ppm formaldehyde, the |
|                    | 0.1, 0.48, or 2.3       | total number of BAL   |
|                    | mg/m^3^), 16 hours/day, | cells, MPs, and       |
|                    | 5 days/week for 12      | eosinophils were      |
|                    | weeks. Six mice at each | increased (9.65       |
|                    | exposure level were     | versus 2.84, 7.22     |
|                    | given intraperitoneal   | versus 2.74, and 2.0  |
|                    | injections of OVA plus  | versus 0.02 ×104      |
|                    | adjuvant before the     | cells, respectively). |
|                    | initial exposure and on |                       |
|                    | weeks 3, 6, 9, and 11   | Levels of IL-1β in    |
|                    | of the experiment. Five | BAL of immunized mice |
|                    | mice at each            | were decreased by     |
|                    | formaldehyde-exposure   | formaldehyde exposure |
|                    | level did not receive   | (p\<0.05 at 1.8 ppm   |
|                    | OVA injections. One day | formaldehyde).        |
|                    | after the last          | Immunization with OVA |
|                    | exposure, spleens were  | significantly         |
|                    | collected and           | increased the         |
|                    | disaggregated and       | neuropeptide nerve    |
|                    | spleen cells harvested  | growth factor (NGF)   |
|                    | for cell culture.       | in BAL. However, this |
|                    | Lymphocyte              | increase with OVA     |
|                    | proliferation in        | immunization was      |
|                    | response to             | attenuated by 0.08    |
|                    | lipopolysaccharide      | and 0.40 ppm          |
|                    | (LPS),                  | formaldehyde          |
|                    | phytohemagglutinin A    | exposure. A similar   |
|                    | (PHA), or OVA was       | response was seen in  |
|                    | determined after 72     | blood plasma NGF      |
|                    | hours in culture.       | levels, where the     |
|                    | Splenocytes were        | increase with OVA     |
|                    | cultured for 48 hours   | immunization was      |
|                    | in the presence of LPS, | attenuated in mice    |
|                    | PHA, and OVA (immunized | exposed to 0.08 and   |
|                    | mice only), and         | 0.40 but not to 1.8   |
|                    | supernatants were       | ppm formaldehyde.     |
|                    | collected for cytokine  | Plasma level of       |
|                    | analysis (IL-4, IL-5,   | Substance P (a        |
|                    | and INF-γ). Splenocytes | mediator of           |
|                    | were cultured for 24    | neurogenic            |
|                    | hours in the presence   | inflammation) was     |
|                    | or absence of OVA to    | increased by          |
|                    | assess chemokine        | formaldehyde          |
|                    | production (MCP-1 and   | exposures in          |
|                    | MIP1-α). Anti-OVA IgE,  | non-immunized mice.   |
|                    | IgG1, IgG2, and IgG3    | Although Substance P  |
|                    | were quantified in      | was increased by OVA  |
|                    | blood plasma.           | immunization, this    |
|                    |                         | again seemed to be    |
|                    |                         | attenuated by         |
|                    |                         | formaldehyde          |
|                    |                         | exposure, reducing    |
|                    |                         | Substance P levels to |
|                    |                         | undetectable levels.  |
|                    |                         |                       |
|                    |                         | Formaldehyde exposure |
|                    |                         | (1.8 ppm) increased   |
|                    |                         | INF-γ fourfold in LPS |
|                    |                         | stimulated cultured   |
|                    |                         | spleen cells from     |
|                    |                         | non-immunized mice.   |
|                    |                         | OVA in vitro          |
|                    |                         | stimulation           |
|                    |                         | significantly         |
|                    |                         | increased the         |
|                    |                         | chemokines MIP-1 and  |
|                    |                         | MCP-1 for control and |
|                    |                         | formaldehyde-treated  |
|                    |                         | OVA-immunized mice.   |
|                    |                         | The OVA stimulated    |
|                    |                         | release of MCP-1 in   |
|                    |                         | vitro was enhanced by |
|                    |                         | formaldehyde exposure |
|                    |                         | in a concentration    |
|                    |                         | dependent manner,     |
|                    |                         | increasing threefold  |
|                    |                         | and fourfold at 0.40  |
|                    |                         | and 1.8 ppm,          |
|                    |                         | respectively.         |
|                    |                         |                       |
|                    |                         | Anti-OVA IgG1 was     |
|                    |                         | slightly depressed in |
|                    |                         | immunized mice        |
|                    |                         | exposed to 0.40 ppm   |
|                    |                         | formaldehyde, and     |
|                    |                         | anti-OVA IgG3 was     |
|                    |                         | depressed in          |
|                    |                         | immunized mice        |
|                    |                         | exposed to 0.08 and   |
|                    |                         | 0.40 ppm              |
|                    |                         | formaldehyde.         |
+--------------------+-------------------------+-----------------------+
| Pulmonary          | **MRID 43167201**       | Formaldehyde did not  |
| Hypersensitivity   |                         | cause increased       |
|                    | Burleigh- Flayer, H. D. | respiratory rate or   |
|                    | and W.J. Kintigh (1992) | altered respiratory   |
|                    | Glutaraldehyde and      | waveform indicative   |
|                    | Formaldehyde: Vapor     | of pulmonary          |
|                    | Pulmonary               | hypersensitivity      |
|                    | Hypersensitivity Study  | during the challenge  |
|                    | in Guinea Pigs. Bushy   | exposures. No         |
|                    | Run Research Center     | mortality, clinical   |
|                    | (Export, PA), Union     | signs, body weight    |
|                    | Carbide. Study ID       | effects, or gross     |
|                    | 92U1123, dated February | lesions were observed |
|                    | 28, 1992, Unpublished.  |                       |
|                    |                         |                       |
|                    | **acceptable**          |                       |
|                    |                         |                       |
|                    | 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       |
|                    | Studies of Immune       | absolute number of    |
| Acute Inhalation   | Function and Host       | monocytes. In the     |
| Toxicity           | Resistance in B6C3F1    | absence of a          |
|                    | Mice Exposed to         | difference in         |
| Purity: 95%        | Formaldehyde.           | recovery of           |
|                    | Toxicology and Applied  | peritoneal cells, the |
|                    | Pharmacology, v.72, p.  | change in monocyte    |
|                    | 519-529.                | number may signal     |
|                    |                         | only a peripheral     |
|                    | **Open Literature**     | response to the local |
|                    |                         | nasal inflammation    |
|                    | 255 Female (SPF) B6C3F1 | and healing which     |
|                    | Mice                    | occurs following HCHO |
|                    |                         | exposure.             |
|                    | 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           |
|                    | al. (1991) Covalent     | cross-links were      |
|                    | Binding of Inhaled      | formed in the         |
|                    | Formaldehyde to DNA in  | respiratory tract of  |
|                    | the Respiratory Tract   | rhesus monkeys        |
|                    | of Rhesus Monkeys:      | exposed to            |
|                    | Pharmacokinetics, Rat-  | formaldehyde.         |
|                    | to-Monkey Interspecies  | Concentrations of     |
|                    | Scaling, and            | cross-links (pmol/mg  |
|                    | Extrapolation to Man.   | DNA) were highest in  |
|                    | Fundamental and Applied | the mucosa of the     |
|                    | Toxicology 17: 409-428. | middle turbinates;    |
|                    |                         | lower concentrations  |
|                    | **Open Literature**     | were produced in the  |
|                    |                         | anterior lateral      |
|                    | 9 Male Rhesus Monkey    | wall/septum and       |
|                    | (*Macaca mulatta*)      | nasopharynx. Very low |
|                    |                         | concentrations were   |
|                    | 14C-Formaldehyde was    | found in the          |
|                    | administered at 0, 0.7, | larynx/trachea/carina |
|                    | 2, or 6 ppm (0, 0.87,   | and in the proximal   |
|                    | 2.5, or 7.4 mg/m^3^)    | portions of the major |
|                    | for 6 hours             | bronchi of some       |
|                    |                         | monkeys exposed to    |
|                    |                         | 7.4 mg/m^3^ but not   |
|                    |                         | to 9.87 mg/m^3^. 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     |
|                    |                         | c                     |
|                    |                         | oncentration-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         | []{.mark}               | Isotopic effect on    |
|                    |                         | DNA-protein           |
|                    | D\'A. Heck, Henry, and  | crosslinking by 3HCHO |
|                    | Merccedes Casanova      | and H-14-CHO:         |
|                    | (1987) Isotope Effects  |                       |
|                    | and Their Implications  | A small (3.4 +- 0.9%) |
|                    | for the Covalent        | isotope effect was    |
|                    | Binding of Inhaled (3H) | detected on this      |
|                    | and (14C) Formaldehyde  | reaction, which       |
|                    | in the Rat Nasal        | slightly favored      |
|                    | Mucosa. Toxicology and  | 3HCHO over H14CHO in  |
|                    | Applied Pharmacology    | binding to DNA. The   |
|                    | 89: 122-134.            | magnitude of this     |
|                    |                         | isotope effect cannot |
|                    | **Open Literature**     | account for the high  |
|                    |                         | isotope ratio         |
|                    | Male F-344 (CDF/ CrIBR) | observed in the       |
|                    | rats                    | crosslinked DNA in    |
|                    |                         | vivo.                 |
|                    | Isotopic effect on      |                       |
|                    | DNA-protein             | Isotopic effect on    |
|                    | crosslinking by 3HCHO   | the oxidation of      |
|                    | and H-14-CHO: Rat       | 3HCHO and H14-CHO:    |
|                    | hepatic nuclei          |                       |
|                    | incubated with 3H and   | 3HCHO is oxidized     |
|                    | 14C formaldehyde        | significantly more    |
|                    |                         | slowly than H14CHO    |
|                    | Isotopic effect on the  | under these           |
|                    | oxidation of 3HCHO and  | conditions. A similar |
|                    | H14-CHO: homogenates of | isotope effect was    |
|                    | the rat nasal mucosa    | observed in the       |
|                    | incubated with 3H       | absence of GSH,       |
|                    | and14C formaldehyde at  | presumably due to the |
|                    | total formaldehyde      | oxidation of 3HCHO    |
|                    | concentrations ranging  | and H14CHO, which can |
|                    | from 0.1 to 11 uM, NAD+ | bind to DNA resulting |
|                    | (1 mM), GSH (15 mM),    | in an isotope ratio   |
|                    | and pyrazole (1mM)      | higher than that of   |
|                    |                         | inhaled gas. The      |
|                    |                         | isotope effect on the |
|                    |                         | oxidation of 3HCHO    |
|                    |                         | and H14CHO suggests   |
|                    |                         | that previous         |
|                    |                         | estimates of the      |
|                    |                         | amount of             |
|                    |                         | formaldehyde          |
|                    |                         | covalently bound to   |
|                    |                         | nasal mucosal DNA may |
|                    |                         | have been too large;  |
|                    |                         | especially at low     |
|                    |                         | airborne              |
|                    |                         | concentrations and    |
|                    |                         | that the shape of the |
|                    |                         | c                     |
|                    |                         | oncentration-response |
|                    |                         | curve for DNA-protein |
|                    |                         | cross linking is more |
|                    |                         | nonlinear than        |
|                    |                         | reported previously.  |
+--------------------+-------------------------+-----------------------+
| Inhalation         | []{.mark}               | **NOAEL: 2.5          |
|                    |                         | mg/m^3^**             |
|                    | Morgan, K. et al.       |                       |
|                    | (1986) Responses of the | **LOAEL: 7.4          |
|                    | Nasal Mucociliary       | mg/m^3^**             |
|                    | Apparatus of 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,      |
|                    | Rat                     | including ocular and  |
|                    |                         | nasal discharge, and  |
|                    | 0, 0.7, 2, 6, or 15 ppm | reddish exudate in    |
|                    | (0, 0.62, 2.5, 7.4, or  | the nasal passages.   |
|                    | 19 mg/m^3^) 6 hour      |                       |
|                    | exposures for up to 3   | Defects in            |
|                    | week duration           | 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 Short   | Monticello, et al.      | **NOAEL: 2.5          |
| and Intermediate   | (1991) Regional         | mg/m^3^**             |
| term               | Increases in Rat Nasal  |                       |
|                    | Epithelial Cell         | **LOAEL: 7.4          |
|                    | Proliferation following | mg/m^3^**             |
|                    | Acute and Subchronic    |                       |
|                    | Inhalation of           | Animals exposed to    |
|                    | Formaldehyde.           | 2.5 mg/m^3^ or less   |
|                    | Toxicology and Applied  | had no microscopic    |
|                    | Pharmacology 111:       | evidence of           |
|                    | 409-421.                | formaldehyde-induced  |
|                    |                         | lesions.              |
|                    | **Open Literature**     | Formaldehyde-induced  |
|                    |                         | lesions at higher     |
|                    | Rats (36/group)         | doses were confined   |
|                    |                         | to nasal passages     |
|                    | 0, 0.7, 2, 6, 10, or 15 | primarily involving   |
|                    | ppm (0, 0.87, 2.5, 7.4, | the                   |
|                    | 12, or 19 mg/m^3^), 6   | cuboidal-transitional |
|                    | hr/day for 1, 4, or 9   | and respiratory       |
|                    | days, or 6 weeks (5     | epithelium. Light     |
|                    | days/week)              | microscopic lesions   |
|                    |                         | were not observed in  |
|                    |                         | the trachea, carina,  |
|                    |                         | or more distal        |
|                    |                         | conducting airways.   |
|                    |                         | Lesions exhibiting an |
|                    |                         | anterior-posterior    |
|                    |                         | severity gradient     |
|                    |                         | varied over exposure  |
|                    |                         | time and were         |
|                    |                         | con                   |
|                    |                         | centration-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 -- Sensory   | []{.mark}               | **RD~50~: 3.84        |
| Irritation         |                         | mg/m^3^**             |
|                    | Kane, Laurel E.; and    |                       |
| Purity: 37%        | Alarie, Yves. (1977)    |                       |
|                    | Sensory Irritation to   |                       |
|                    | Formaldehyde and        |                       |
|                    | Acrolein During Single  |                       |
|                    | and Repeated Exposures  |                       |
|                    | in Mice. American       |                       |
|                    | Industrial Hygiene      |                       |
|                    | Association Journal,    |                       |
|                    | v.38, p. 509-522.       |                       |
|                    |                         |                       |
|                    | **Open Literature**     |                       |
|                    |                         |                       |
|                    | M SPF Swiss Webster     |                       |
|                    | Mouse (4/group)         |                       |
|                    |                         |                       |
|                    | Mice were exposed via   |                       |
|                    | inhalation for 3        |                       |
|                    | hours/day for 4 days to |                       |
|                    | a concentration of      |                       |
|                    | formaldehyde that would |                       |
|                    | be expected to produce  |                       |
|                    | a 30% decrease in       |                       |
|                    | respiratory rate within |                       |
|                    | the first 10 minutes of |                       |
|                    |                         |                       |
|                    | exposure (as predicted  |                       |
|                    | by the                  |                       |
|                    |                         |                       |
|                    | concentration-response  |                       |
|                    | relationship) or to an  |                       |
|                    | atmosphere containing a |                       |
|                    | concentration equal to  |                       |
|                    | 1/10 the RD50 for       |                       |
|                    | formaldehyde for 3      |                       |
|                    | hr/day for 3 days.      |                       |
+--------------------+-------------------------+-----------------------+
| Other - Sensory    | []{.mark}               | **RD50: 3.2 ppm       |
| Irritation         |                         | (2.1--4.7 ppm) (Swiss |
|                    | Steinhagen, WH; Barrow, | Webster)**            |
|                    | CS. (1984) Sensory      |                       |
|                    | irritation              | **RD50: 4.90 ppm      |
|                    | structure-activity      | (3.9--6.4 ppm)        |
|                    | study of inhaled        | (B6C3F1)**            |
|                    | aldehydes in B6C3F1 and |                       |
|                    | Swiss-Webster mice.     | The difference in     |
|                    | Toxicol Appl Pharmacol  | results between       |
|                    | 72:495-503. (NCEA)      | strains was not       |
|                    |                         | statistically         |
|                    | **Open Literature**     | significant. On the   |
|                    |                         | average, α, β         |
|                    | M Swiss Webster and     | unsaturated aliphatic |
|                    | B6C3F1 mice (3-4/dose)  | aldehydes and         |
|                    |                         | formaldehyde were     |
|                    | 10 minute head-only     | approximately 2       |
|                    | exposure to             | orders of magnitude   |
|                    | formaldehyde and other  | more potent than      |
|                    | aldehydes               | 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           | []{.mark}               | []{.mark}             |
|                    |                         |                       |
| Other - Sensory    | Gardner, RJ; Burgess,   | **RD50: 13.8 ppm**    |
| Irritation         | BA; Kennedy, GL, Jr.    |                       |
|                    | (1985) Sensory          | Estimate was about    |
| Purity: 5%         | irritation potential of | threefold less than   |
|                    | selected nasal          | the 31.7 ppm reported |
|                    | tumorigens in the rat.  | for male F344 rats    |
|                    | Food Chem Toxicol       | (Barrow et al.,       |
|                    | 23:87-92.               | 1983). This may       |
|                    |                         | indicate differences  |
|                    | []{.mark}               | in responsiveness to  |
|                    |                         | formaldehyde among    |
|                    | **Open Literature**     | different strains of  |
|                    |                         | rat. Concentrations   |
|                    | 8-week-old Crl-CD male  | of 5.5 ppm or more    |
|                    | rats (4/group)          | produced considerable |
|                    |                         | depression in         |
|                    | []{.mark}               | respiratory rate. The |
|                    |                         | decrease was observed |
|                    | The RD50 of eight       | during the first      |
|                    | chemicals was           | minute of exposure    |
|                    | determined to determine | and achieved a        |
|                    | whether there was a     | maximum at about 3    |
|                    | correlation between the | minutes. Some         |
|                    | ability of a chemical   | recovery was observed |
|                    | to produce sensory      | during exposure from  |
|                    | irritation and          | 3 to 10 minutes after |
|                    | tumorigenic potency.    | the start but was     |
|                    | Groups of rats were     | incomplete during the |
|                    | exposed for 15 minutes  | first 5 minutes after |
|                    | to various              | exposure. Taking the  |
|                    | concentrations of       | results of the eight  |
|                    | formaldehyde ranging    | chemicals together,   |
|                    | from 0.77 to 24.9 ppm   | sensory irritation    |
|                    | after a 5-minute        | potency did not       |
|                    | pretest exposure to     | correlate with the    |
|                    | control air.            | carcinogenic potency  |
|                    |                         | indicated by          |
|                    | []{.mark}               | long-term inhalation  |
|                    |                         | experiments.          |
+--------------------+-------------------------+-----------------------+
| 870.1300           | []{.mark}               | Exposure to           |
|                    |                         | formaldehyde at 15    |
| Other - Sensory    | Chang, JC; Barrow, CS.  | ppm for 6 hours/day,  |
| Irritation         | (1984) Sensory          | 5 days/week failed to |
|                    | irritation tolerance    | induce tolerance.     |
| Purity: 95%        | and cross-tolerance in  | However, tolerance    |
| paraformaldehyde   | F-344 rats exposed to   | was observed          |
|                    | chlorine or             | following exposure to |
|                    | formaldehyde gas.       | 28 ppm formaldehyde   |
|                    | Toxicol Appl Pharmacol  | for 4 days. The       |
|                    | 76:319-327.             | c                     |
|                    |                         | oncentration-response |
|                    | []{.mark}               | curve in these        |
|                    |                         | animals was           |
|                    | **Open Literature**     | significantly         |
|                    |                         | different than that   |
|                    | []{.mark}               | of naïve animals,     |
|                    |                         | with an increase in   |
|                    | M Fischer 344 (CDF\[F   | RD50 estimate for     |
|                    | 344\]Crl/Br) rats       | this exposure         |
|                    | (4/group)               | duration from 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.      | 4.7--13.7)**          |
| Other - Sensory    | (1996) Sensory          |                       |
| Irritation         | irritation to mixtures  |                       |
|                    | of formaldehyde,        |                       |
| Purity: 90%-92%    | acrolein, and           |                       |
| Paraformaldehyde   | acetaldehyde in rats.   |                       |
|                    | Arch Toxicol            |                       |
|                    | 70:329-337. (NCEA)      |                       |
|                    |                         |                       |
|                    | **Open Literature**     |                       |
|                    |                         |                       |
|                    | M Wistar rats (4/dose)  |                       |
|                    |                         |                       |
|                    | Cassee et al. (1996)    |                       |
|                    | determined the RD50     |                       |
|                    | values for              |                       |
|                    | formaldehyde,           |                       |
|                    | acetaldehyde, and       |                       |
|                    | acrolein as a result of |                       |
|                    | a 30-minute nose-only   |                       |
|                    | exposure.               |                       |
+--------------------+-------------------------+-----------------------+
| 870.1300           | []{.mark}               | []{.mark}             |
|                    |                         |                       |
| Other - Sensory    | Kulle, TJ; Cooper, GP.  | **The mean thresholds |
| Irritation         | (1975) Effects of       | were 0.25 ppm for     |
|                    | formaldehyde and ozone  | formaldehyde**, 5.0   |
| Purity: 95%        | on the trigeminal nasal | ppm for ozone, and    |
| Paraformaldehyde   | sensory system. Arch    | 0.30 ppm for amyl     |
|                    | Environ Health          | alcohol.              |
|                    | 30:237-243. (NCEA)      |                       |
|                    |                         | There was a           |
|                    | **Open Literature**     | progressive           |
|                    |                         | depression in         |
|                    | Adult M Sprague-Dawley  | response to amyl      |
|                    | rats (5/experiment)     | alcohol with          |
|                    |                         | increasing stimulus   |
|                    | []{.mark}               | of formaldehyde       |
|                    |                         | concentration \[p \<  |
|                    | The effects of          | 0.01, analysis of     |
|                    | formaldehyde on         | variance (ANOVA)\].   |
|                    | trigeminal nerve        | The effects of        |
|                    | afferent activity in    | exposure to 2.0 ppm   |
|                    | rats was investigated.  | were similar          |
|                    | Electrodes were         | regardless of whether |
|                    | implanted through a     | it was presented      |
|                    | dissection in the right | immediately as a      |
|                    | eye orbit. The authors  | separate exposure or  |
|                    | state that because the  | as the final          |
|                    | ethmoid nerve and       | concentration of a    |
|                    | trigeminal nerve        | progressively         |
|                    | responded similarly the | increasing series.    |
|                    | experiments were        | The response to amyl  |
|                    | performed with the      | alcohol did not fully |
|                    | nasopalatine nerve to   | recover within the    |
|                    | eliminate potential     | 1-hour extended       |
|                    | contribution from the   | recovery period. Thus |
|                    | mechanoreceptor fibers  | it appeared that the  |
|                    | in the ethmoid nerve.   | afferent function     |
|                    | The sensory threshold   | depression was not    |
|                    | was determined by       | due to receptor       |
|                    | extrapolation from the  | adaptation or         |
|                    | measured nerve response | insufficient time for |
|                    | to a range of           | formaldehyde          |
|                    | formaldehyde            | diffusion away from   |
|                    | concentrations          | receptor sites.       |
|                    | (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.                |                       |
|                    |                         |                       |
|                    | []{.mark}               |                       |
+--------------------+-------------------------+-----------------------+
| 870.1300           | []{.mark}               | []{.mark}             |
|                    |                         |                       |
| Other - Sensory    | Tsubone, H; Kawata, M.  | The vapor             |
| Irritation         | (1991) Stimulation to   | concentration         |
|                    | the trigeminal afferent | associated with a 50% |
|                    | nerve of the nose by    | increase in nerve     |
|                    | formaldehyde, acrolein, | activity over the     |
|                    | and acetaldehyde gases. | level of control gas  |
|                    | Inhal Toxicol           | was calculated as     |
|                    | 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.         |                       |
|                    |                         |                       |
|                    | []{.mark}               |                       |
+--------------------+-------------------------+-----------------------+
| Sensory Irritation | **MRID No. 43170601**   | No treatment related  |
|                    |                         | mortality was         |
| Formaldehyde, Lot  | Werley et al. (1994).   | observed. Mice        |
| No. 420807, 10     | Glutardehyde and        | exposed to            |
| %a.i. (methanol    | Formaldehyde: Sensory   | formaldehyde showed   |
| free)              | Irritation Study in     | no treatment-related  |
|                    | Swiss-Webster Mice.     | clinical findings.    |
|                    | Union Carbide Lab       | All mice exposed to   |
|                    | Project No. 91U0123.    | formaldehyde at       |
|                    |                         | 99.1mg/m3 showed      |
|                    | **Supplementary**       | increased lacrimation |
|                    |                         | and periocular        |
|                    | Male Swiss-Webster ND4  | wetness. Slight       |
|                    | mice (40-55 days old at | reductions in body    |
|                    | start of study), 4      | weight were observed  |
|                    | animals/dose            | in some of the mice   |
|                    |                         | at the highest        |
|                    | 0, 0.34, 1.4, 6.9,      | exposure doses for    |
|                    | 18.8, or 80.0 ppm (0,   | formaldehyde.         |
|                    | 0.42, 1.73, 8.55, 23.3, |                       |
|                    | or 99.1 mg/m^3^), 30    |                       |
|                    | min, head-only chambers |                       |
+--------------------+-------------------------+-----------------------+
| Immunologic        | Tarkowski, M. and       | Following             |
| Sensitization      | Gorski, P. 1995.        | sensitization, titer  |
|                    | Increased IgE           | of serum              |
|                    | antiovalbumin level in  | anti-ovalbumin IgE    |
|                    | mice exposed to         | antibodies were       |
|                    | formaldehyde. Int.      | significantly higher  |
|                    | Arch. Allergy Immunol.  | in mice exposed to    |
|                    | 106: 422--424.          | formaldehyde 6        |
|                    |                         | hours/day for 10      |
|                    | **Open Literature**     | days, compared to     |
|                    |                         | mice exposed 6        |
|                    | F Balb/c Mouse          | hours/week for 7      |
|                    |                         | weeks or untreated.   |
|                    | Groups were exposed to  | The authors concluded |
|                    | 2 mg/m^3^ formaldehyde  | that formaldehyde     |
|                    | either 6 hours/day for  | facilitates animal    |
|                    | 10 days, or to 6        | sensitization to      |
|                    | hours/day once a week   | ovalbumin through     |
|                    | for 7 weeks. Then all   | histological changes  |
|                    | mice were sensitized    | occurring in the      |
|                    | intranasally with       | upper respiratory     |
|                    | ovalbumin.              | tract.                |
+--------------------+-------------------------+-----------------------+
| Immunologic        | Riedel, F., et al.      | Following ovalbumin   |
| Sensitization      | C.H.L. 1996.            | challenge, 10/12      |
|                    | Formaldehyde Exposure   | animals exposed to    |
|                    | Enhances Sensitization  | 310 ug/m^3^ showed    |
|                    | in the Guinea Pig.      | bronchial             |
|                    | Allergy 51: 94--99.     | obstruction, compared |
|                    |                         | with 3/12 control     |
|                    | **Open Literature**     | animals (p\<0.01);    |
|                    |                         | animals exposed to    |
|                    | Guinea Pig (12/group)   | 160 ug/m^3^ were not  |
|                    |                         | significantly         |
|                    | Animals were exposed to | different from        |
|                    | formaldehyde            | controls.             |
|                    | concentrations of 0     | Anti-ovalbumin IgG    |
|                    | (controls), 160 or 310  | antibodies were not   |
|                    | ug/m^3^ (0.13 and 0.25  | detectable (\<10      |
|                    | ppm) for 5 days,        | ELISA units or EU) in |
|                    | followed by             | any animal at day 0,  |
|                    | sensitization to        | but were detectable   |
|                    | inhaled ovalbumin at    | in 0/12 controls,     |
|                    | days 5 and 19. On day   | 3/12 animals exposed  |
|                    | 26, a bronchial         | to 160 ug/m^3^, and   |
|                    | provocation test with   | 6/12 animals exposed  |
|                    | ovalbumin was           | to 310 ug/m^3^ at day |
|                    | performed, followed by  | 25.                   |
|                    | 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.             |                       |
+--------------------+-------------------------+-----------------------+
| Immunological      | []{.mark}               | Mice exposed to 15    |
|                    |                         | ppm formaldehyde for  |
|                    | Jakab, GJ. (1992)       | the 4 hours following |
|                    | Relationship between    | bacterial infection   |
|                    | carbon black            | (Regimen A) had       |
|                    | particulate-bound       | approximately an 8%   |
|                    | formaldehyde, pulmonary | increase in bacteria, |
|                    | antibacterial defenses, | indicating decreased  |
|                    | and alveolar macrophage | host resistance       |
|                    | phagocytosis. Inhal     | (p=0.006).            |
|                    | Toxicol 4:325-342.      | Pre-infection         |
|                    |                         | exposure to 0.5 or    |
|                    | **Open Literature**     | 1.0 ppm did not       |
|                    |                         | change bacterial      |
|                    | White Female Swiss      | loading 4 hours after |
|                    | Mouse                   | infection (Regimen    |
|                    |                         | B). However,          |
|                    | Mice were exposed to    | combining an 18-hour  |
|                    | formaldehyde after      | pre-infection         |
|                    | bacterial infection     | formaldehyde exposure |
|                    | (Regimens A and C),     | with a 4-hour         |
|                    | before bacterial        | post-infection 1 ppm  |
|                    | infection (Regimen B),  | formaldehyde exposure |
|                    | or before and after     | increased pulmonary   |
|                    | infection (Regimen D).  | bacterial loading by  |
|                    | In the first trial mice | approximately 6.5%    |
|                    | were exposed to 0, 1.0, | (p\<0.05). Increased  |
|                    | 5.0, 10.0, or 15.0 ppm  | bacterial loading     |
|                    | formaldehyde (0, 1.2,   | indicates that        |
|                    | 6.2, 12.3, or 18.5      | formaldehyde exposure |
|                    | mg/m^3^). The remaining | (Regimens A and D)    |
|                    | mice were exposed to 0, | reduced pulmonary     |
|                    | 0.5, or 1.0 ppm         | bacterial resistance. |
|                    | formaldehyde (0, 6.2,   | This is in apparent   |
|                    | or 1.2 mg/m^3^). A      | contradiction to the  |
|                    | 30-minute exposure to   | findings of increased |
|                    | an infectious aerosol   | host resistance by    |
|                    | of S. aureus deposited  | Dean et al. (1984).   |
|                    | 2x105 staphylococci in  | However, there are    |
|                    | the lungs. Bacterial    | important differences |
|                    | loading was determined  | between the studies.  |
|                    | in homogenized lung     | The studies by Jakab  |
|                    | tissue by culturing     | (1992) are acute      |
|                    | diluted aliquots for an | studies examining     |
|                    | estimate of bacteria    | effects at the        |
|                    | present immediately     | respiratory tract     |
|                    | after loading and 4     | where direct effects  |
|                    | hours later.            | 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              | []{.mark}               | Exposure of mice to   |
|                    |                         | 19 mg/m^3^, 6 hr/day, |
|                    | Adams, D.O. et al.      | 5 days/week for 3     |
|                    | (1987) The Effect of    | weeks did not         |
|                    | Formaldehyde Exposure   | appreciably alter the |
|                    | upon the Mononuclear    | number of resident    |
|                    | Phagocyte System of     | macrophages in the    |
|                    | Mice. Toxicology and    | peritoneal cavit+y or |
|                    | Applied Pharmacology    | that elicited in      |
|                    | 88: 165-174.            | response to MVE-2.    |
|                    |                         |                       |
|                    | **Open Literature**     |                       |
|                    |                         |                       |
|                    | Female Mouse            |                       |
|                    |                         |                       |
|                    | 15 ppm (19 mg/m^3^), 6  |                       |
|                    | hr/day, 5 days/week. 3  |                       |
|                    | weeks                   |                       |
+--------------------+-------------------------+-----------------------+
| Other              | []{.mark}               | Under non --occlusive |
|                    |                         | conditions,           |
|                    | Bartnik, F.G.,          | absorption of         |
|                    | Gloxhuber Chr., and     | radiolabeled          |
|                    | Zimmermann V. (1985)    | formaldehyde in the   |
|                    | Percutaneous Absorption | cosmetic cream        |
|                    | of Formaldehyde in      | preparation was       |
|                    | Rats. Toxicology        | published as 6.1% in  |
|                    | Letters. v. 25. p.      | males and 9.2% in     |
|                    | 167 - 172.              | females. Occlusive    |
|                    |                         | conditions reported   |
|                    | **Open Literature**     | absorption as 3.4% in |
|                    |                         | males.                |
|                    | 10 Male/4 Female Rat    |                       |
|                    |                         |                       |
|                    | \[14C\] Formaldehyde as |                       |
|                    | a tracer and            |                       |
|                    | non-labeled             |                       |
|                    | formaldehyde were       |                       |
|                    | incorporated into a     |                       |
|                    | cream and dermally      |                       |
|                    | applied at 200 mg to    |                       |
|                    | occluded and            |                       |
|                    | nonocclusive dosing     |                       |
|                    | areas for 48 hours      |                       |
+--------------------+-------------------------+-----------------------+
| Other              | Hester, et al. (2003)   | Siginificance         |
|                    | Formaldehyde-Induced    | analysis of           |
|                    | Gene Expression in F344 | microarrays (SAM)     |
|                    | Rat Nasal Respiratory   | hybridization data    |
|                    | Epithelium. Toxicology  | revealed that 24 of   |
|                    | 187: 13-24. (NCEA)      | the 1185 genes        |
|                    |                         | queried were          |
|                    | **Open Literature**     | significantly         |
|                    |                         | up-regulated and 22   |
|                    | 8 F344 Male Rats        | genes were            |
|                    |                         | significantly         |
|                    | 40 ul aliquots of water | downregulated. The    |
|                    | or formaldehyde (400    | identified genes with |
|                    | mM) were instillled     | FA-induced change in  |
|                    | into nostrils using a   | expression belong to  |
|                    | pipette. Twenty-four    | the functional gene   |
|                    | hours after treatment,  | categories xenobiotic |
|                    | nasal epithelium was    | metabolism, cell      |
|                    | recovered from which    | cycle, apoptosis, and |
|                    | total RNA was used to   | DNA repair. These     |
|                    | generate cDNA probes.   | data suggest that     |
|                    |                         | multiple pathways are |
|                    |                         | dysregulated by       |
|                    |                         | formaldehyde          |
|                    |                         | exposure, including   |
|                    |                         | those involved in DNA |
|                    |                         | synthesis/repair and  |
|                    |                         | regulation of cell    |
|                    |                         | proliferation.        |
+--------------------+-------------------------+-----------------------+
| 870.3100           | Vargova M, Wagnerova J, | **NOAEL: 40           |
|                    | Liskova A, et al.       | mg/kg/day**           |
| Other              | (1993) Subacute         |                       |
|                    | immunotoxicity study of | **LOAEL: 80           |
| Purity: 28.44%     | formaldehyde in male    | mg/kg/day** for an    |
|                    | rats. Drug Chem Toxicol | increase in the       |
|                    | 16:255-275.             | incidence of          |
|                    |                         | hepatocelluar         |
|                    | **Open Literature**     | vacuolization         |
|                    |                         |                       |
|                    | 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           | []{.mark}               | **NOAEL: 2.5          |
|                    |                         | mg/m^3^**             |
| Other              | Casanova, Mercedes, et  |                       |
|                    | al. (1994) DNA-Protein  | **LOAEL: 7.4          |
| Purity: 14-C       | Cross-links and Cell    | mg/m^3^**             |
| Paraformaldehyde   | Replication at Specific |                       |
| (97.3-99%),        | Sites in the Nose of    | Visible lesions were  |
|                    | F344 Rats Exposed       | only observed in      |
| Unlabeled          | Subchronically to       | animals exposed to    |
| paraformaldehyde   | Formaldehyde.           | 18.6 mg/m^3^ for 12   |
| (95%)              | Fundamental and Applied | weeks. No             |
|                    | Toxicology 23: 525-536. | formaldehyde-induced  |
|                    |                         | lesions were observed |
|                    | **Open Literature**     | in the squamous and   |
|                    |                         | olfactory regions of  |
|                    | Rats inhalation (20     | the nose. Rats        |
|                    | rats/group, 10 of which | exposed to 0.87 or    |
|                    | are preexposed (PE), 10 | 2.5 mg/m^3^ were      |
|                    | not (N))                | indistinguishable     |
|                    |                         | from controls. At 7.4 |
|                    | 0.7, 2, 6, 10, or 15    | mg/m^3^, lesions were |
|                    | ppm (0, 0.87, 2.5, 7.4, | confined to           |
|                    | 12.4, or 18.6 mg/m^3^)  | multifocal epithelial |
|                    | Preexposed animals      | hypertrophy,          |
|                    | whole-body exposed 6    | hyperplasia, and      |
|                    | hr/day, 11 weeks +4     | squamous metaplasia   |
|                    | days) On the 5th day of | of the lM, while the  |
|                    | the 12th week, animals  | rest of the nose was  |
|                    | exposed once nose-only  | unaffected. At 12.39  |
|                    | for 3 hours H14-CHO     | mg/m^3^, the most     |
|                    | using nominal           | characteristic        |
|                    | concentrations DPX      | response was squamous |
|                    | estimation: 6 ppm or 10 | metaplasia of the     |
|                    | ppm (7.4 or 12.4        | transitional          |
|                    | mg/m^3^) On 5th day of  | epithelial lining of  |
|                    | 12th week, exposed to   | the LM and medial     |
|                    | unlabeled formaldehyde  | maxilloturbinate, and |
|                    | once nose-only for 3    | mild epithelial       |
|                    | hours using nominal     | hyperplasia of the    |
|                    | concentration           | midseptum with        |
|                    |                         | generally mild        |
|                    |                         | inflammatory cell     |
|                    |                         | infiltration.         |
|                    |                         |                       |
|                    |                         | 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^.         |
+--------------------+-------------------------+-----------------------+

**5.0 Toxicity Endpoint Selection**

**5.1 See Section 7.1, Summary of Toxicological Doses and Endpoint
Selection**

> **5.2 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 radiolabelled 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.
>
> **5.3 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
    animal toxicity 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

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-   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 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 \[in press\]).

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-   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.

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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 (Hauptmann et al., 2003, 2004). 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=viewChemical.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.

6.  **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.

**7.0 Summary of Toxicological Doses and Endpoints for Formaldehyde for
use in Risk Assessment**

+--------------+---------------+-----------------+--------------------+
| **Table 5    |               |                 |                    |
| 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      |                 |                    |
+--------------+---------------+-----------------+--------------------+

**8.0 Toxicity Profile Tables**

### 8.1 Acute Toxicity Profile Table - (See Section 4.1, Acute Toxicity, Table 2).

### 8.2 Subchronic, Chronic and Other Toxicity Profiles Table (Table 6)

+--------------------+-------------------------+-----------------------+
| **Table 6.         |                         |                       |
| Subchronic,        |                         |                       |
| Chronic and Other  |                         |                       |
| Toxicity Profiles  |                         |                       |
| for Formaldehyde** |                         |                       |
+====================+=========================+=======================+
| **Guideline        | **MRID Number (Year)/** | **Results**           |
| Number/**          |                         |                       |
|                    | **Citation/**           |                       |
| **Study Type/**    | **Classification/       |                       |
|                    | Doses**                 |                       |
| **Test Substance   |                         |                       |
| (% a.i.)**         |                         |                       |
+--------------------+-------------------------+-----------------------+
| **Subchronic       |                         |                       |
| Toxicity**         |                         |                       |
+--------------------+-------------------------+-----------------------+
| 870.3100           | **MRID 00124677**       | **NOAEL: 0.3%**       |
|                    |                         | formaldehyde          |
| 90-Day oral        | Driedger, A.; Walker,   |                       |
| toxicity in        | J.; Galloway, F. (1973) | **LOAEL: 0.6%**       |
| rodents            | Letter sent to C. Smart | formaldehyde, based   |
|                    | dated Oct 1, 1973: "Rat | on irritability,      |
| Purity: 37% a.i.   | tolerance to Dietary    | weight loss, hair     |
|                    | Formaldehyde: Reference | loss, yellowing of    |
|                    | No. AD-114-73,          | teeth, and decreased  |
|                    | JRW-341-73."            | food consumption      |
|                    | (Unpublished study;     |                       |
|                    | submitted by Celanese   | Rats exposed to       |
|                    | Chemical Co., Dallas,   | concentrations of     |
|                    | TX; CDL:094622-H)       | 0.6% formaldehyde and |
|                    |                         | higher exhibited      |
|                    | 10 male Holtzman        | dose-related          |
|                    | rats/dose               | increases in          |
|                    |                         | irritability,         |
|                    | 0, 0.3, 0.6, 1.2, or    | disability, hair      |
|                    | 2.4 % formaldehyde      | loss, and yellowing   |
|                    |                         | of teeth and          |
|                    |                         | dose-related          |
|                    |                         | 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 |
| 28-Day oral        | Viguera, C.; Kundzins,  | body weight gains and |
| toxicity in        | M. (1960) "28-Day Oral  | total food            |
| rodents            | Administration\--Rats:  | consumption revealed  |
|                    | U.F. Concentrate-85\|." | no significant        |
| Purity: 60% a.i.   | (Unpublished study;     | differences between   |
|                    | prepared by Hazleton    | the control group and |
|                    | Laboratories, Inc.;     | test groups. The      |
|                    | CDL: 105284-C)          | appearance and        |
|                    |                         | behavior of the test  |
|                    | 10 Male Sprague-Dawley  | rats were comparable  |
|                    | rats/dose               | to those of the       |
|                    |                         | control rats. No      |
|                    | 0, 79, 158, or 316      | pathological findings |
|                    | uL/kg/day, once daily,  | associated with the   |
|                    | 5 days/ week, 20 doses  | oral administration   |
|                    |                         | of the test substance |
|                    |                         | were observed.        |
|                    |                         |                       |
|                    |                         | One rat exposed to    |
|                    |                         | 158 uL/kg/day died    |
|                    |                         | during the 4th week.  |
|                    |                         | Autopsy revealed a    |
|                    |                         | pale, mottled liver.  |
|                    |                         | Three rats receiving  |
|                    |                         | the high dose of      |
|                    |                         | formaldehyde showed   |
|                    |                         | slight salivation     |
|                    |                         | during the 4th week   |
|                    |                         | of the study.         |
+--------------------+-------------------------+-----------------------+
| 870.3100           | Johannsen, F.R., G.J.   | **NOAEL: 50 mg/kg/day |
|                    | Levinskas A.S. Tegris   | (M), 100 mg/kg/day    |
| 90-Day oral        | (1986) Effects of       | (F)**                 |
| toxicity in        | Formaldehyde in the Rat |                       |
| rodents            | and Dog following Oral  | **LOAEL: 100          |
|                    | Exposure. Toxicology    | mg/kg/day (M), 150    |
| Purity: 95% a.i.,  | Letters 30: 1-6. (NCEA) | mg/kg/day (F)**,      |
| aqueous            |                         | based on decreased    |
| paraformaldehyde   | **Open Literature**     | body weight gain      |
|                    |                         |                       |
|                    | Sprague-Dawley Albino   | No deaths or abnormal |
|                    | Rat                     | reactions were        |
|                    |                         | observed in rats      |
|                    | (15/sex/dose)           | administered          |
|                    |                         | formaldehyde for 90   |
|                    | Formaldehyde was        | days. Significant     |
|                    | administered in the     | reductions in weight  |
|                    | drinking-water at       | gain were observed in |
|                    | target doses of 0, 50,  | both sexes at 150     |
|                    | 100, or 150 mg/kg bw/d  | mg/kg and in male     |
|                    | for 13 weeks (91        | rats given 100 mg/kg. |
|                    | consecutive days)       | There was a           |
|                    |                         | dose-related decrease |
|                    |                         | in liquid consumption |
|                    |                         | in both male rats     |
|                    |                         | (9%, 18%, and 31%)    |
|                    |                         | and females (13%,     |
|                    |                         | 22%, and 30%)         |
|                    |                         | administered          |
|                    |                         | formaldehyde in their |
|                    |                         | drinking water. There |
|                    |                         | were no overall       |
|                    |                         | differences in mean   |
|                    |                         | food intake or feed   |
|                    |                         | efficiency in rats at |
|                    |                         | any test level, thus  |
|                    |                         | reductions in body    |
|                    |                         | weight gain are       |
|                    |                         | considered to be a    |
|                    |                         | reflection of         |
|                    |                         | systemic effects of   |
|                    |                         | formaldehyde. No      |
|                    |                         | stat                  |
|                    |                         | istically-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.       | **NOAEL= 25           |
|                    | (1988) Evaluation of    | mg/kg/day**           |
| 28-Day oral        | the Oral Toxicity of    |                       |
| toxicity in        | Acetaldehyde and        | **LOAEL = 125         |
| rodents            | Formaldehyde in a       | mg/kg/day**, based on |
|                    | 4-week Drinking Water   | yellowish fur from    |
| Paraformaldehyde   | Study in Rats. Fd.      | week 3 onward,        |
| (95% a.i.,         | Chem. Toxic. 26(5):     | decreased food        |
| aqueous)           | 447-452. (NCEA)         | intake, decreased     |
|                    |                         | protein and albumin   |
|                    | **Open Literature**     | levels in blood       |
|                    |                         | plasma, and           |
|                    | Rat (10/sex/dose)       | histologic changes.   |
|                    |                         |                       |
|                    | 0, 5, 25, or 125        | There were no deaths  |
|                    | mg/kg/day; a            | and the rats appeared |
|                    | water-restricted group  | healthy throughout    |
|                    | (10/sex) received the   | the study.            |
|                    | same amount of water as |                       |
|                    | liquid consumed by the  | The fur of the rats   |
|                    | high-dose groups        | receiving 125         |
|                    |                         | mg/kg/day showed a    |
|                    |                         | yellowish             |
|                    |                         | discoloration from    |
|                    |                         | week 3                |
|                    |                         |                       |
|                    |                         | onwards. Food intake  |
|                    |                         | of animals receiving  |
|                    |                         | the high dose was     |
|                    |                         | significantly lower,  |
|                    |                         | whereas females       |
|                    |                         | receiving the low-    |
|                    |                         | and mid- dose groups  |
|                    |                         | had increased food    |
|                    |                         | intake. There were no |
|                    |                         | significant changes   |
|                    |                         | in hematology among   |
|                    |                         | the test groups.      |
|                    |                         | Total protein and     |
|                    |                         | albumin levels in the |
|                    |                         | blood plasma were     |
|                    |                         | decreased in males in |
|                    |                         | the high dose.        |
|                    |                         | Relative kidney       |
|                    |                         | weights were          |
|                    |                         | increased at 125      |
|                    |                         | mg/kg/day (p\>0.05).  |
|                    |                         | Histologic            |
|                    |                         | examination of test   |
|                    |                         | groups revealed:      |
|                    |                         | focal hyperkeratosis  |
|                    |                         | of the forestomach    |
|                    |                         | (20/20); Focal        |
|                    |                         | gastritis (3/10       |
|                    |                         | males, 3/10 females); |
|                    |                         | submucosal            |
|                    |                         | mononuclear-cell      |
|                    |                         | infiltrate (1/10      |
|                    |                         | males); focal         |
|                    |                         | papillomatous         |
|                    |                         | hyperplasia (1/10     |
|                    |                         | females); and         |
|                    |                         | polymorphonuclear     |
|                    |                         | leukocytic            |
|                    |                         | infiltration (1/10    |
|                    |                         | females).             |
|                    |                         |                       |
|                    |                         | The water- restricted |
|                    |                         | group had slightly    |
|                    |                         | higher blood cell     |
|                    |                         | values in males.      |
|                    |                         | Clinical chemistry    |
|                    |                         | and blood plasma      |
|                    |                         | changes observed      |
|                    |                         | include: increased    |
|                    |                         | urea in males and     |
|                    |                         | females; decreased    |
|                    |                         | bilirubin levels and  |
|                    |                         | increased chloride    |
|                    |                         | and sodium levels in  |
|                    |                         | males and decreased   |
|                    |                         | sodium, calcium, and  |
|                    |                         | phosphorus in         |
|                    |                         | females. Increased    |
|                    |                         | relative organ        |
|                    |                         | weights were observed |
|                    |                         | in male gonads        |
|                    |                         | (p\<0.01), brains     |
|                    |                         | (males: p\<0.05,      |
|                    |                         | females: p\<0.01),    |
|                    |                         | male hearts           |
|                    |                         | (p\<0.01), kidneys    |
|                    |                         | (p\<0.01), and in the |
|                    |                         | liver (males:         |
|                    |                         | p\<0.01, females:     |
|                    |                         | p\<0.05). Histopath   |
|                    |                         | examination revealed  |
|                    |                         | dilated fundic glands |
|                    |                         | (2/10) in males.      |
+--------------------+-------------------------+-----------------------+
| 870.3150           | 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          |
| nonrodents         | and Dog following Oral  | mg/kg/day (M/F)**,    |
|                    | Exposure. Toxicology    | based on reduced      |
| Purity:            | Letters 30: 1-6. (NCEA) | weight gain           |
| Paraformaldehyde   |                         |                       |
| (95% a.i.,         | **Open Literature**     | No deaths or abnormal |
| aqueous)           |                         | reactions were        |
|                    | Beagle Dog (4/sex/dose) | observed. Significant |
|                    |                         | reductions in weight  |
|                    | 0, 50, 75, or 100       | gain were observed in |
|                    | mg/kg/day in drinking   | both sexes at 100     |
|                    | water for 90 days       | mg/kg/day. Treated    |
|                    |                         | animals had reduced   |
|                    |                         | food consumption and  |
|                    |                         | feed efficiency even  |
|                    |                         | at the lower dosages  |
|                    |                         | (50 and 75 mg/kg/day) |
|                    |                         | which did not depress |
|                    |                         | weight gain.          |
|                    |                         | Hematological values  |
|                    |                         | from treated dogs     |
|                    |                         | fell within normal    |
|                    |                         | limits.No specific    |
|                    |                         | treatment-related     |
|                    |                         | effects were observed |
|                    |                         | on any organ or       |
|                    |                         | tissue, including     |
|                    |                         | possible target       |
|                    |                         | organs like the       |
|                    |                         | kidney, liver, and    |
|                    |                         | lung.                 |
+--------------------+-------------------------+-----------------------+
| 870.3465           | **MRID 00082134**       | One of the 15 rats    |
|                    |                         | died; none of the     |
| 90-Day inhalation  | Coon, R.A. et al.       | other animals showed  |
| toxicity           | (1970) Animal           | signs of illness or   |
|                    | Inhalation Studies on   | toxicity. Hematologic |
|                    | Ammonia, Ethylene       | values were normal.   |
|                    | Glycol, Formaldehyde,   | On histopathologic    |
|                    | Dimethylamine, and      | examination, the      |
|                    | Ethanol. Toxicology and | lungs of all species  |
|                    | Applied Pharmacology    | consistently showed   |
|                    | 16: 646-655. (NCEA)     | varying degrees of    |
|                    |                         | interstitial          |
|                    | 15 Sprague-Dawley and   | inflammation. The     |
|                    | Long-Evans rats (M/F),  | hearts and kidneys    |
|                    | 15 Princeton-derived    | from guinea pigs and  |
|                    | guinea pigs (M/F), 3    | rats showed focal     |
|                    | New Zealand rabbits     | chronic inflammatory  |
|                    | (M), 3 squirrel monkeys | changes.              |
|                    | (M), 2 Beagle dogs (M)  |                       |
|                    |                         |                       |
|                    | Formaldehyde Continuous |                       |
|                    | exposure to 4.6         |                       |
|                    | mg/m^3^, 8 hours/day, 5 |                       |
|                    | days/week, 6 weeks      |                       |
+--------------------+-------------------------+-----------------------+
| 870.3465           | []{.mark}               | []{.mark}             |
|                    |                         |                       |
| 6-Week inhalation  | **MRID 00149755**       | Treatment-related     |
| toxicity           |                         | effects during the    |
|                    | Rusch, G.; Rinehart, W. | study were not seen.  |
| Purity = 4.96%     | (1980) A 26 Week        | Compared to controls, |
|                    | Inhalation Toxicity     | monkeys receiving     |
|                    | Study of Formaldehyde   | 1.00 ppm showed       |
|                    | in Monkey, Rat, and     | increased incidence   |
|                    | Hamster: Project No.    | of dried material     |
|                    | 79- 7259. Unpublished   | around the nose,      |
|                    | study prepared by       | increased incidences  |
|                    | Bio/dynamics Inc. 184   | of hoarseness and     |
|                    | p.                      | congestion.           |
|                    |                         |                       |
|                    | []{.mark}               | [Body                 |
|                    |                         | weight]{.underline}   |
|                    | Fisher 344 rats --      |                       |
|                    | 10/sex/dose; Syrian     | Compared to controls, |
|                    | golden hamsters --      | no significant body   |
|                    | 10/sex/doseand          | weight changes were   |
|                    | Cynomolgous monkeys --  | seen for monkeys and  |
|                    | 6 males/dose            | hamsters throughout   |
|                    |                         | the study. The 3 ppm  |
|                    | []{.mark}               | male and female rats  |
|                    |                         | showed significant    |
|                    | Test material           | differences (p ≤      |
|                    | (Formaldehyde, Lot      | 0.01) from week 2-26  |
|                    | #0611N-79) was          | compared to controls. |
|                    | administered at 0, 0,   |                       |
|                    | 0.20, 1.00, or 3.00 ppm | [Organ                |
|                    | equivalent to 0, 0,     | weight]{.underline}   |
|                    | 0.19, 0.98 and 2.95     |                       |
|                    | ppm, respectively, for  | Organ weights for     |
|                    | 26 weeks.               | monkeys and hamsters  |
|                    |                         | were not              |
|                    | []{.mark}               | significantly         |
|                    |                         | different compared to |
|                    |                         | controls. Male and    |
|                    |                         | female rats in the    |
|                    |                         | 0.2 ppm group had     |
|                    |                         | significant mean      |
|                    |                         | heart weight          |
|                    |                         | depression (p ≤ 0.01) |
|                    |                         | compared to the       |
|                    |                         | control. Males in the |
|                    |                         | 3.0 ppm test group    |
|                    |                         | had significantly (p  |
|                    |                         | ≤ 0.01) depressed mea |
|                    |                         | absolute heart and    |
|                    |                         | kidney weights        |
|                    |                         | compared to the       |
|                    |                         | controls, but the     |
|                    |                         | relative weights of   |
|                    |                         | these same tissues    |
|                    |                         | were significantly    |
|                    |                         | increased for these   |
|                    |                         | same rats. Females in |
|                    |                         | the 3.0 ppm test      |
|                    |                         | group had             |
|                    |                         | significantly (p ≤    |
|                    |                         | 0.01) depressed       |
|                    |                         | absolute heart        |
|                    |                         | weights with the mean |
|                    |                         | relative heart weight |
|                    |                         | significantly         |
|                    |                         | increased (p ≤ 0.01). |
|                    |                         | For the 3 ppm group,  |
|                    |                         | the mean absolute and |
|                    |                         | relative liver        |
|                    |                         | weights were          |
|                    |                         | significantly         |
|                    |                         | depressed (p ≤ 0.01)  |
|                    |                         | compared to the       |
|                    |                         | controls.             |
|                    |                         |                       |
|                    |                         | [Gross and            |
|                    |                         | Microscopic           |
|                    |                         | P                     |
|                    |                         | athology]{.underline} |
|                    |                         |                       |
|                    |                         | In monkeys, hamsters  |
|                    |                         | and rats, no          |
|                    |                         | abnormalities were    |
|                    |                         | seen in or            |
|                    |                         | attributable to       |
|                    |                         | formaldehyde vapors.  |
+--------------------+-------------------------+-----------------------+
| 870.3465           | []{.mark}               | **NOAEL: 1.2          |
|                    |                         | mg/m^3^**             |
| 90-Day inhalation  | Woutersen, R.A. et al.  |                       |
| toxicity           | (1987) Subchronic       | **LOAEL: 12 mg/m^3^** |
|                    | (13-week) Inhalation    |                       |
| Purity: 97-99%     | Toxicity Study of       | In the high-dose      |
| a.i.               | Formaldehyde in Rats.   | group, uncoordinated  |
|                    | Journal of Applied      | locomotion, and       |
|                    | Toxicology, 7(1):       | climbing of the cage  |
|                    | 43-49.                  | walls were observed   |
|                    |                         | only during the 1st   |
|                    | **Open Literature**     | 30 minutes of each    |
|                    |                         | exposure period.      |
|                    | Rats (10/sex/dose)      | Stat                  |
|                    |                         | istically-significant |
|                    | 0, 1.0, 10, or 20 ppm   | growth retardation    |
|                    | (0, 1.2, 12, or 24      | occurred in males and |
|                    | mg/m^3^), 6 hr/day, 5   | females of the        |
|                    | days/week               | 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           | []{.mark}               | **NOAEL = 1.24        |
|                    |                         | mg/m^3^**             |
| 90-Day inhalation  | Appelman, L.M. et al.   |                       |
| toxicity           | (1988) One-year         | **LOAEL = 12.4        |
|                    | Inhalation Toxicity     | mg/m^3^**, based on   |
|                    | Study of Formaldehyde   | body weight           |
|                    | in Male Rats with a     | retardation,          |
|                    | Damaged or Undamaged    | incidence of          |
|                    | Nasal Mucosa. Journal   | oliguria, and         |
|                    | of Applied Toxicology,  | incidence of lesions  |
|                    | 8(2): 85-90.            | of the respiratory    |
|                    |                         | and olfactory         |
|                    | **Open Literature**     | epitheliums for       |
|                    |                         | damaged and undamaged |
|                    | Male albino Wistar rats | animals               |
|                    | (Cpb:WU) -40/dose       |                       |
|                    |                         | The nose damaged by   |
|                    | Formaldehyde exposure   | electrocoagulation is |
|                    | via inhalation route    | more susceptible to   |
|                    | for 6 hr/day, 5         | cytotoxic action of   |
|                    | days/week, 13 or 52     | formaldehyde than the |
|                    | weeks at concentrations | undamaged nose.       |
|                    | of 0.1, 1, or 10 ppm    |                       |
|                    | (0, 0.12, 1.24, or 12.4 | 8 animals (7 with     |
|                    | mg/m^3^), 1/2 with      | damaged and 1 with    |
|                    | bilaterally damaged     | undamaged nose)       |
|                    | nasal mucosa            | randomly distributed  |
|                    |                         | among control and     |
|                    |                         | test groups, had to   |
|                    |                         | be killed in extremis |
|                    |                         | or were found dead.   |
|                    |                         | Growth retardation    |
|                    |                         | was observed in       |
|                    |                         | animals with or       |
|                    |                         | without a damaged     |
|                    |                         | nose after 2 weeks    |
|                    |                         | exposure to 12.4      |
|                    |                         | mg/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       |
|                    |                         | th                    |
|                    |                         | inning/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           | []{.mark}               | []{.mark}             |
|                    |                         |                       |
| 90-Day inhalation  | Chemical Industry       | **NOAEL = 4 ppm       |
| toxicity           | Institute of Technology | (LDT)**               |
|                    |                         |                       |
|                    | 20 Mice and Rats        | **Systemic LOAEL =    |
|                    |                         | 12.7 ppm,** based on  |
|                    | Test material           | body weight decrease  |
|                    | administered at         | and nasal erosion.    |
|                    | concentrations of 4,    |                       |
|                    | 12.7, or 38.6 ppm for 6 | No adverse effects    |
|                    | hours each day, five    | observed in the 4 ppm |
|                    | days a week for 13      | group. At 12.7 ppm, a |
|                    | weeks.                  | decrease in body      |
|                    |                         | weight and evidence   |
|                    | []{.mark}               | of nasal erosion in   |
|                    |                         | two exposed rats was  |
|                    |                         | observed. Ulceration  |
|                    |                         | and necrosis of the   |
|                    |                         | nasal mucosa seen at  |
|                    |                         | 38.6 ppm resulted in  |
|                    |                         | termination of        |
|                    |                         | exposure after 2      |
|                    |                         | weeks.                |
+--------------------+-------------------------+-----------------------+
| 870.3465           | []{.mark}               | []{.mark}             |
|                    |                         |                       |
| 90-Day inhalation  | Test material           | **Systemic NOAEL =    |
| toxicity           | administered at         | 0.028 ppm**           |
|                    | concentrations of       |                       |
| Purity             | 0.0098, 0.028, 0.82, or | **Systemic LOAEL =    |
|                    | 2.4 ppm for 3 months.   | 0.82 ppm,** base don  |
|                    |                         | proliferation of      |
|                    | 25 Rats                 | lymphocytes,          |
|                    |                         | histiocytes in the    |
|                    | []{.mark}               | lungs, perivascular   |
|                    |                         | hyperemia.            |
|                    |                         |                       |
|                    |                         | **ChE NOAEL = 0.82    |
|                    |                         | ppm**                 |
|                    |                         |                       |
|                    |                         | **ChE LOAEL = 2.4     |
|                    |                         | ppm**                 |
|                    |                         |                       |
|                    |                         | At 2.4 ppm there was  |
|                    |                         | a significant         |
|                    |                         | decrease in           |
|                    |                         | cholinesterase        |
|                    |                         | activity; at 2.4 and  |
|                    |                         | 0.82 ppm, there was   |
|                    |                         | proliferation of      |
|                    |                         | lymphocytes and       |
|                    |                         | histiocytes in the    |
|                    |                         | lungs and some        |
|                    |                         | peribronchial and     |
|                    |                         | perivascular          |
|                    |                         | hyperemia. There were |
|                    |                         | no significant        |
|                    |                         | findings at the two   |
|                    |                         | lower concentrations. |
+--------------------+-------------------------+-----------------------+
| 870.3465           | []{.mark}               | []{.mark}             |
|                    |                         |                       |
| 90-Day inhalation  | Dubreuil, A., G.        | **NOAEL = 1.6 ppm**   |
| toxicity           | Bouley, J. Godin, and   |                       |
|                    | C. Boudène. (1976).     | The only adverse      |
|                    | Continuous inhalation   | effect seen at 1.6    |
|                    | of low-level doses of   | ppm was discoloration |
|                    | formaldehyde:           | of hair. The 4.55 ppm |
|                    | Experimental study on   | group was exposed for |
|                    | the rat. Eur. J.        | 45 days and had a     |
|                    | Toxicol. 9:245-250.     | decrease in rate of   |
|                    |                         | weight gain. The 8.07 |
|                    | **Open Literature**     | ppm was exposed for   |
|                    |                         | 60 days and has       |
|                    | []{.mark}               | respiratory and eye   |
|                    |                         | irritation, a         |
|                    | 25 rats                 | decrease in food      |
|                    |                         | consumption, and a    |
|                    | []{.mark}               | decease in liver      |
|                    |                         | weight.               |
|                    | Test material           |                       |
|                    | administered at         |                       |
|                    | concentrations of 1.6,  |                       |
|                    | 4.55, or 8.07 ppm for   |                       |
|                    | 45-90 days.             |                       |
|                    |                         |                       |
|                    | []{.mark}               |                       |
+--------------------+-------------------------+-----------------------+
| **Developmental    |                         |                       |
| Toxicity**         |                         |                       |
+--------------------+-------------------------+-----------------------+
| 870.3700a          | **MRID 00082136,        | Formalin exposure     |
|                    | 00123770**              | resulted in small,    |
| Prenatal           |                         | subcutaneous          |
| Developmental      | Schnurer, Lars- Bentil  | necroses. No          |
| Toxicity           | (1963) Maternal and     | differences in smear  |
|                    | Fetal Responses to      | cytology were noted   |
| Purity: 35% a.i.   | Chronic Stress in       | between the pregnant  |
|                    | Pregnancy: A Study in   | treated and pregnant  |
|                    | Albino Rats. Acta       | control rats.         |
|                    | Endocrinologica,        |                       |
|                    | Supplement 80: 1-96.    | No stress-induced     |
|                    |                         | changes of the        |
|                    | Rats (56, 67, 50,       | gastric mucosa were   |
|                    | 44/group, respectively) | seen. The following   |
|                    |                         | treatment- related    |
|                    | Subcutaneous injection, | organ weight changes  |
|                    | Pregnant rats exposed   | were observed:        |
|                    | to 0.25 mL of 2%        | thyroid weight was    |
|                    | solution, pregnant      | significantly lower   |
|                    | control rats,           | in                    |
|                    | non-pregnant rats       | formaldehyde-exposed  |
|                    | exposed to 0.25 mL of   | non-pregnant rats;    |
|                    | 2%, control non-        | adrenal weights       |
|                    | pregnant rats; 2x/day,  | increased             |
|                    | GD 2-19 to 22           | significantly in      |
|                    |                         | exposed non-pregnant  |
|                    |                         | rats.                 |
|                    |                         |                       |
|                    |                         | Formaldehyde- exposed |
|                    |                         | pregnant rats yielded |
|                    |                         | 56 litters, totaling  |
|                    |                         | 551 fetuses. Pregnant |
|                    |                         | controls yielded 67   |
|                    |                         | litters, 662 fetuses. |
|                    |                         | Formaldehyde-exposed  |
|                    |                         | rats had heavier      |
|                    |                         | fetuses than          |
|                    |                         | controls. No          |
|                    |                         | instances of          |
|                    |                         | malformed limbs or    |
|                    |                         | cleft palate were     |
|                    |                         | observed. Fetal       |
|                    |                         | thyroid and adrenal   |
|                    |                         | weight reductions may |
|                    |                         | be due to passage of  |
|                    |                         | corticosteroids from  |
|                    |                         | exposed mothers to    |
|                    |                         | fetuses.              |
+--------------------+-------------------------+-----------------------+
| 870.3700a          | **MRID 00164652**       | Maternal Toxicity:    |
|                    |                         |                       |
| Prenatal           | Marks, Thomas A. et al. | **NOAEL = 0           |
|                    | (1980) Influence of     | mg/kg/day**           |
| Developmental      | Formaldehyde and        |                       |
|                    | Sonacide (Potentiated   | **LOAEL = 74          |
| Toxicity (rodent)  | Acid Glutaraldehyde) on | mg/kg/day**, based on |
|                    | Embryo and Fetal        | decreased body weight |
| Purity: Fischer    | Development in Mice.    | gain.                 |
| certified ACS      | Teratology 22: 51-58.   |                       |
| solution, contains |                         | The 185 mg/kg/day     |
| 12-15% methanol    | Oral gavage             | dose of formaldehyde  |
|                    | (76/29/35/34            | was clearly toxic; 22 |
|                    | animals/dose) 0, 74,    | of the 34 pregnant    |
|                    | 148, or 185 mg/kg/day,  | mice died before day  |
|                    | GD 6-15                 | 18. Methanol, 12-15%  |
|                    |                         | of the original       |
|                    | Female CD-1 Mice        | solution, may have    |
|                    |                         | contributed to this   |
|                    |                         | toxicity. There was   |
|                    |                         | also a significant    |
|                    |                         | decrease in average   |
|                    |                         | weight gain during    |
|                    |                         | pregnancy at 74       |
|                    |                         | mg/kg/day. The test   |
|                    |                         | solution did not have |
|                    |                         | a significant effect  |
|                    |                         | in the incidence of   |
|                    |                         | malformed mouse       |
|                    |                         | fetuses. Doses of 148 |
|                    |                         | and 74 mg/kg/day had  |
|                    |                         | no significant effect |
|                    |                         | on the unborn         |
|                    |                         | offspring or on the   |
|                    |                         | pregnant dam.         |
+--------------------+-------------------------+-----------------------+
| 870.3700a          | []{.mark}               | Maternal Toxicity:    |
|                    |                         |                       |
| Prenatal           | Saillenfait, A.M., et   | **NOAEL = 24.8        |
|                    | al (1989) The effects   | mg/m^3^**             |
| Developmental      | of maternally inhaled   |                       |
|                    | formaldehyde on         | **LOAEL = 49.6        |
| Toxicity           | embryonal and foetal    | mg/m^3^**, based on   |
|                    | development in rats.    | decreased body weight |
| Purity: 37% a.i.   | Fd. Chem. Toxic. 27(8): | gain                  |
|                    | 545-548. (NCEA)         |                       |
|                    |                         | Offspring Toxicity:   |
|                    | **Open Literature**     |                       |
|                    |                         | **NOAEL = 12.4        |
|                    | Female Sprague-Dawley   | mg/m^3^**             |
|                    | rats (25/dose)          |                       |
|                    |                         | **LOAEL = 24.8        |
|                    | 0, 5, 10, 20, or 40 ppm | mg/m^3^**, based on   |
|                    | (0, 6.2, 12.4, 24.8, or | reduced fetal         |
|                    | 49.6 mg/m^3^) for 6     |                       |
|                    | 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          | []{.mark}               | Treatment had no      |
|                    |                         | effect on maternal    |
| Prenatal           | Overman, D.O. (1984)    | weight gain. The      |
|                    | Absence of Embryotoxic  | treatment did not     |
| Developmental      | Effects of Formaldehyde | influence fetal C- R  |
|                    | after Percutaneous      | length. Mean fetal    |
| Toxicity (rodent)  | Exposure in Hamsters.   | weight was slightly   |
|                    | Toxicology Letters 24:  | increased in          |
| Purity: 37% a.i.   | 107-110.                | experimental animals, |
|                    |                         | but the difference    |
|                    | **Open Literature**     | was not               |
|                    |                         | stati                 |
|                    | Pregnant Charles river  | stically-significant. |
|                    | Lak:LVG (SYR) Golden    | Two fetuses from the  |
|                    | strain hamsters --      | same litter after     |
|                    | Number of animals not   | treatment on day 8    |
|                    | reported                | were significantly    |
|                    |                         | smaller than their    |
|                    | 0.5 mL, 2 hours/day, GD | litter mates (\>3 SD  |
|                    | 8-11                    | 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 and   | Hurni, H. and H. Odher  |                       |
| fertility effects  | (1972) Reproduction     | The treatments did    |
|                    | Study with Formaldehyde | not affect the        |
| Purity: 40% a.i.   | and                     | pregnancy rate. The   |
|                    | Hexamethylenetetr-amine | body weight increased |
|                    | in Beagle Dogs. Fd.     | regularly during      |
|                    | Cosmet. Toxicol. 11:    | pregnancy in all      |
|                    | 459-462.                | groups and the        |
|                    |                         | duration of gestation |
|                    | 51 female Beagle dogs   | was unaffected by the |
|                    |                         | treatments. The mean  |
|                    | 0, 3.1, or 9.4          | litter size was       |
|                    | mg/kg/day               | within the normal     |
|                    |                         | range for all groups, |
|                    |                         | demonstrating that    |
|                    |                         | fecundity was not     |
|                    |                         | affected by           |
|                    |                         | treatment. Neither    |
|                    |                         | the adult dogs nor    |
|                    |                         | their litters showed  |
|                    |                         | any signs of          |
|                    |                         | physiological or      |
|                    |                         | skeletal              |
|                    |                         | abnormalities or      |
|                    |                         | disorders of          |
|                    |                         | reproduction.         |
+--------------------+-------------------------+-----------------------+
| 870.3800           | []{.mark}               | 200 mg/kg: A          |
|                    |                         | statistically         |
| Reproduction and   | Cassidy, S.L., K.M.     | significant increase  |
| fertility effects  | Dix, and T. Jenkins     | in total sperm heads  |
|                    | (1983) Evaluation of a  | per gram testis, as   |
| Purity: 40% a.i.   | testicular sperm head   | well as an increase   |
|                    | counting technique      | in percentage of      |
|                    | using rats exposed to   | abnormal sperm heads. |
|                    | dimethoxyethyl          | Data indicated that   |
|                    | phthalate (DMEP),       | \"the induction of    |
|                    | glycerol                | increased levels of   |
|                    | a-monochlorohydrin      | abnormal sperm may be |
|                    | (GMCH), epichlorohydrin | a measurable index of |
|                    | (ECH), formaldehyde     | the mutagenic         |
|                    | (FA), or methyl         | potential of a        |
|                    | methanesulphonate       | chemical for          |
|                    | (MMS). Arch. Toxicol.   | mammalian germ        |
|                    | 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     |
|                    | Northwest Laboratories. | 123.93 mg/m^3^ or     |
| Chronic Toxicity   | (1980)                  | greater produced 100% |
|                    |                         | mortality. The highly |
| Purity: 9.20%      | \"Tracor Jitco          | irritating nature of  |
|                    | Inhalation              | this chemical was     |
|                    | Carcinogenesis          | evident               |
|                    | Bioassay: Repeated Dose | microscopically in    |
|                    | Study Report on         | all dose levels       |
|                    | Formaldehyde.\"         | examined, ranging     |
|                    |                         | from minimal to mild  |
|                    | **Open Literature**     | supportive rhinitis   |
|                    |                         | in the 18.59 mg/m^3^  |
|                    | B6C3F1 Mouse            | dose level dose       |
|                    | (5/sex/group)           | level, to necrosis    |
|                    |                         | and sloughing of the  |
|                    | Mice were exposed to    | mucosa in the         |
|                    | one of five             | turbinates, trachea,  |
|                    | concentrations of       | and proximal bronchi  |
|                    | vaporized formaldehyde  | in the 61.96 mg/m^3^  |
|                    | for a period of 6 hours | animals.              |
|                    | per day for a total of  |                       |
|                    | ten exposures. The      | Differential weight   |
|                    | target concentrations   | gains of both male    |
|                    | were 15, 25, 50, 100,   | and female mice at    |
|                    | and 200 ppm (18.59,     | 18.59, 30.98, and     |
|                    | 30.98, 61.96, 123.93,   | 61.96 mg/m^3^ was     |
|                    | and 247.85 mg/m^3^).    | significant as        |
|                    |                         | 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          | []{.mark}               | **NOAEL: 0.4          |
|                    |                         | mg/m^3^**             |
| Chronic Toxicity   | Kamata, Eiichi et al.   |                       |
|                    | (1997) Results of a     | **LOAEL: 2.5          |
| Purity: 37% a.i.   | 28-month Chronic        | mg/m^3^**             |
|                    | Inhalation Toxicity     |                       |
|                    | Study of Formaldehyde   | Nasal tumors were     |
|                    | in Male Fischer-344     | macroscopically       |
|                    | Rats. The Journal of    | evident in the 19     |
|                    | Toxicological Sciences  | mg/m^3^ group from    |
|                    | 22(3): 239-254.         | the 14th month.       |
|                    |                         | Histopathological     |
|                    | **Open Literature**     | examination revealed  |
|                    |                         | squamous cell         |
|                    | Male Fischer 344 rats   | papillomas and        |
|                    | (32/dose)               | carcinomas. No nasal  |
|                    |                         | tumors were observed  |
|                    | 0, 0.3, 2, or 15 ppm    | in the lower exposure |
|                    | (0, 0.4, 2.5, or 19     | groups (0.4 and 2.5   |
|                    | mg/m^3^), 6hr/day, 5    | mg/m^3^ groups). In   |
|                    | days/week via           | the 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.         |
+--------------------+-------------------------+-----------------------+
| *                  |                         |                       |
| *Carcinogenicity** |                         |                       |
+--------------------+-------------------------+-----------------------+
| 870.4200a          | **MRID 00143288**       | 0.6% to 0.8%:         |
|                    |                         | necrosis, the         |
| Oncogenicity (Rat) | Watanabe, F., et al.    | formation of an       |
|                    | (1954) Study on the     | ulcer, while the area |
|                    | Carcinogenicity of      | around the injection  |
|                    | Aldehyde. 1st Report.   | spot formed a tuber   |
|                    | Experimentally Produced | which was very        |
|                    | Rat Sarcomas by         | difficult to heal     |
|                    | Repeated Injections of  |                       |
|                    | Aqueous Solution of     | 0.4% - 0.5%: rare     |
|                    | Formaldehyde. Two       | occurrence of an      |
|                    | unpublished             | ulcer. After two to   |
|                    | translations of         | five months after     |
|                    | Japanese article        | having stopped the    |
|                    | published in Gann       | injections            |
|                    | 45(2-3):451-452.        | observations revealed |
|                    |                         | the occurrence of     |
|                    | Rat                     | sarcomas either at    |
|                    |                         | the injection spot or |
|                    | Repeated subcutaneous   | in the internal       |
|                    | injections of 1 cc of   | organs of 4 out of 10 |
|                    | an aqueous formaldehyde | of the rats.          |
|                    | 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. | []{.mark}             |
|                    | Uchida, et al. 1985.    |                       |
| Oncogenicity (Rat) | Studies of the          | During the exposure   |
|                    | inhalation toxicity of  | running noses,        |
|                    | formaldehyde. National  | running tears and     |
|                    | Sanitary and Medical    | crouching were seen   |
|                    | Laboratory Service      | in the 15 ppm dose    |
|                    | (Japan). p. 1-94.       | group. These symptoms |
|                    |                         | decreased as the      |
|                    | []{.mark}               | number of exposures   |
|                    |                         | increased. Hair       |
|                    | **Open Literature**     | around the abdominal  |
|                    |                         | region was observed   |
|                    | []{.mark}               | to be yellow in color |
|                    |                         | and bleeding from the |
|                    | 32 Male Fischer 344     | forelimbs was seen.   |
|                    | rats/dose               | Yellow discoloration  |
|                    |                         | of abdominal hair was |
|                    | []{.mark}               | also seen in the 2.0  |
|                    |                         | ppm dose group        |
|                    | Test material was       | although it was       |
|                    | administered at         | light. Significant    |
|                    | concentrations of 0,    | suppression of weight |
|                    | 0.3, 2.0 or 15 ppm in   | gain and a decrease   |
|                    | aqueous solution        | in the amount of food |
|                    | methanol, 6 hours/day,  | gain were seen in the |
|                    | 5 days/week for 28      | 15 ppm dose group. 20 |
|                    | months. The exposure at | of 24 animals in the  |
|                    | 15 ppm was tested for   | 15 ppm dose group     |
|                    | 24 months. A positive   | died in the 24 month  |
|                    | control -- 3.3 ppm      | dosing period giving  |
|                    | methanol and a          | a high death rate of  |
|                    | nonexposure (NE)        | 88.3%.                |
|                    | control were also used. |                       |
|                    |                         | Recognizable tumors   |
|                    | []{.mark}               | were observed in the  |
|                    |                         | 15 ppm group from the |
|                    |                         | 420^th^ day onwards   |
|                    |                         | and tumors were       |
|                    |                         | recognized            |
|                    |                         | 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      |
|                    | Effects of Ethanol,     | produce malignant     |
| Oncogenicity (Rat) | Potassium               | tumors when given     |
|                    | Metabisulfate,          | alone. Forestomach    |
|                    | Formaldehyde, and       | papillomas occurred   |
|                    | Hydrogen Peroxide on    | in 8/10 animals       |
|                    | Gastric Carcinogenesis  | administered formalin |
|                    | in Rats after           | alone.                |
|                    | Initiation with N-      |                       |
|                    | methyl-N\'nit           | In the group          |
|                    | ro-N\'nitrosoguanidine. | administered both MNG |
|                    | Jap. J. Cancer Res. 77: | and formalin,         |
|                    | 118-124.                | forestomach           |
|                    |                         | papillomas occurred   |
|                    | **Open Literature**     | in 15/17 animals,     |
|                    |                         | adenocarcinoma of the |
|                    | Male Wistar rats        | pylorus in 4/17,      |
|                    |                         | preneoplastic         |
|                    | A two-stage             | hyperplasia of the    |
|                    | carcinogenesis bioassay | pylorus in 7/17, and  |
|                    | was conducted in which  | adenocarcinoma of the |
|                    | N-methyl-N\'nitro-      | duodenum in 1/17.     |
|                    | 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           |
|                    | (1986) Formaldehyde and | granulomas in the     |
| Oncogenicity       | Skin Carcinogenesis.    | lung; slight          |
|                    | Environ Int 12:541-544. | hyerplasia of the     |
| (Mouse)            |                         | epidermis, small skin |
|                    | **Open Literature**     | ulcers                |
| 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 |
|                    | Chromey and J.W.        | mg caused mild to     |
| Oncogenicity       | McAlack, \"Skin         | moderate skin         |
|                    | initiation- promotion   | irritation, whereas 1 |
| (Mouse)            | study with formaldehyde | mg caused only mild   |
|                    | in CD-1 mice\", E.I. du | irritation.           |
| Purity: 10%        | Pont de Nemours &       |                       |
|                    | Company, Inc. In:       | As expected, BaP/TPA  |
|                    | Formaldehyde:           | gave a high tumor     |
|                    | Toxicology,             | yield (28/29 mice, 9  |
|                    | Epidemiology, and       | of which had          |
|                    | Mechanisms, Clary,      | malignant tumors.     |
|                    | J.J., J.E. Gibson, and  | Benign test site      |
|                    | R.S. Waritz, Eds.,      | tumors were           |
|                    | N.Y., Marcel Dekker,    | keratoacanthomas or   |
|                    | Inc., 1983.             | squamous papillomas.  |
|                    |                         | No other combinations |
|                    | **Open Literature**     | gave yields           |
|                    |                         | significantly         |
|                    | Female CD-1 Mouse       | different from        |
|                    |                         | controls. Thus the    |
|                    | Mice were treated on    | test is negative      |
|                    | shaved dorsal skin with | under study           |
|                    | up to 10 mg             | conditions, with the  |
|                    | formaldehyde, followed  | caveat that one       |
|                    | by repeated doses.      | cannot be certain     |
|                    | Formaldehyde was also   | whether formaldehyde  |
|                    | applied once at 5       | underwent significant |
|                    | mg/mouse to assess      | degradation to formic |
|                    | initiation potential.   | acid or other         |
|                    | Promoter potential was  | products.             |
|                    | tested at 0.1, 0.5,     |                       |
|                    | and1.0 mg/mouse,        |                       |
|                    | applied 3 times/wk for  |                       |
|                    | 26 wk. Positive         |                       |
|                    | controls \[150 mg       |                       |
|                    | benzo(a)pyrene (BaP) as |                       |
|                    | initiator, 2.5 mg 12-O- |                       |
|                    | tetradecanoyl           |                       |
|                    | phorbol-13-acetate(TPA) |                       |
|                    | as promoter\], or       |                       |
|                    | negative control        |                       |
|                    | (acetone) were used.    |                       |
+--------------------+-------------------------+-----------------------+
| 870.4200b          | Spangler, F. and J.M.   | Study found no        |
|                    | Ward, \"Skin            | evidence of           |
| Oncogenicity       | initiation/promotion    | formaldehyde as an    |
|                    | study with formaldehyde | initiating agent, nor |
| (Mouse)            | in Sencar mice\". Study | as a complete         |
|                    | location:               | carcinogen, however   |
| Purity: 3.7%-4%    | Microbiological         | investigators         |
|                    | Associates (Bethesda,   | considered there to   |
|                    | MD) in conjunction with | be \"a slight         |
|                    | NCI. In: Formaldehyde:  | possibility that      |
|                    | Toxicology,             | formaldehyde may be a |
|                    | Epidemiology, and       | very, very weak       |
|                    | Mechanisms, Clary,      | promoting agent\",    |
|                    | J.J., J.E. Gibson, and  | based on a very small |
|                    | R.S. Waritz, Eds.,      | tumor yield when      |
|                    | N.Y., Marcel Dekker,    | formaldehyde was      |
|                    | Inc., 1983.             | tested as a promoter  |
|                    |                         | in mice treated with  |
|                    | **Open Literature**     | DMBA.                 |
|                    |                         |                       |
|                    | Female Sencar Mice      |                       |
|                    | (30/group)              |                       |
|                    |                         |                       |
|                    | Mice were treated in    |                       |
|                    | various combinations    |                       |
|                    | with or without an      |                       |
|                    | initiator (DMBA) or     |                       |
|                    | promoter                |                       |
|                    | \[12-O-t                |                       |
|                    | etradecanoylphorbol-13- |                       |
|                    | acetate (TPA)\]. 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     |
| Purity: Not        | 9-14.                   | unexposed controls.   |
| reported           |                         | No tumors were        |
|                    | **Open Literature**     | observed in the       |
|                    |                         | respiratory tract of  |
|                    | 88 male Syrian golden   | non-exposed hamsters  |
|                    | hamsters                | or of those exposed   |
|                    |                         | to formaldehyde.      |
|                    | Test material was       | There was, therefore, |
|                    | administered at a 10    | no evidence of        |
|                    | ppm concentration 5     | carcinogenic activity |
|                    | times/week for          | of formaldehyde under |
|                    | lifetime.               | the given exposure    |
|                    |                         | conditions.           |
|                    |                         |                       |
|                    |                         | Little evidence of    |
|                    |                         | toxicity from         |
|                    |                         | formaldehyde exposure |
|                    |                         | was observed in the   |
|                    |                         | nasal epithelium,     |
|                    |                         | expected to be a      |
|                    |                         | prime target issue.   |
|                    |                         | There was no increase |
|                    |                         | in the incidence of   |
|                    |                         | rhinitis related to   |
|                    |                         | exposure (observed in |
|                    |                         | 31% of untreated      |
|                    |                         | animals and 24% of    |
|                    |                         | the                   |
|                    |                         | formaldehyde-exposed  |
|                    |                         | hamsters).            |
|                    |                         | Hyperplastic and      |
|                    |                         | metaplstic areas were |
|                    |                         | each observed in the  |
|                    |                         | nasal epithelium of   |
|                    |                         | 5% of hamsters        |
|                    |                         | exposed to            |
|                    |                         | formaldehyde while    |
|                    |                         | none were observed in |
|                    |                         | control animals.      |
+--------------------+-------------------------+-----------------------+
| 870.4300           | **MRID 00143289**       | From exposure weeks 3 |
|                    |                         | to 103, mildly (15    |
| Chronic/           | Kerns, W.D. et al.      | to35 g) decreased     |
| Oncogenicity       | (1983) Carcinogenicity  | body weights          |
|                    | of Formaldehyde in Rats | (p\<0.05) in male and |
| Purity: Not        | and Mice after          | female rats (6.9 and  |
| Reported           | Long-Term Inhalation    | 18 mg/m^3^) were      |
|                    | Exposure. Cancer        | observed. Animals in  |
|                    | Research 43: 4382-4392. | the 2.5 mg/m^3^       |
|                    |                         | exposure group had    |
|                    | Rat (Fischer 344) and   | sporadically reduced  |
|                    | Mice (B6C3F~1~) -       | body weights          |
|                    | approx 120/sex/dose     | (p\>0.05) throughout  |
|                    |                         | the exposure period.  |
|                    | 0, 2.0, 5.6, or 14.3    | Male and female rats  |
|                    | ppm (0, 2.5, 6.9, or 18 | in the 18 mg/m3       |
|                    | mg/m^3^), 6 hrs/day, 5  | exposure group        |
|                    | days/week, up to 24     | exhibited             |
|                    | months                  | significantly         |
|                    |                         | increased mortality   |
|                    |                         | (p\<0.001) from the   |
|                    |                         | 12th month onward.    |
|                    |                         | Male rats in the      |
|                    |                         | intermediate exposure |
|                    |                         | groups showed a       |
|                    |                         | stat                  |
|                    |                         | istically-significant |
|                    |                         | co                    |
|                    |                         | ncentration-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                     |
|                    |                         | co                    |
|                    |                         | ncentration-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    |
|                    |                         | c                     |
|                    |                         | oncentration-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^.              |
+--------------------+-------------------------+-----------------------+
| **Neurotoxicity**  |                         |                       |
+--------------------+-------------------------+-----------------------+
| 870.6200           | Malek, FA; Moritz, KU;  | Malek et al. (2003a): |
|                    | Fanghanel, J. (2003a)   |                       |
| Neurotoxicity      | Formaldehyde inhalation | **LOAEL = 1.0 ppm, 2  |
| screening battery  | and open field          | hours**               |
|                    | behaviour in rats. Ind  |                       |
| Purity:            | J Med Res 118:90-96.    | In general, sniffing  |
|                    | (NCEA)                  | was increased after   |
| (2003a) - 37%      |                         | formaldehyde exposure |
| stock solution was | Malek, FA; Moritz, K-U; | and movement was      |
| used to prepare    | Fanghaenel, J. (2003b)  | decreased (crossed    |
| solutions of 0.5%, | A study on specific     | quadrants and         |
| 1%, and 2.5%       | behavioral effects of   | climbing) in both     |
|                    | formaldehyde in the     | male and female rats  |
| (2003b) -- 0.1%,   | rat. J Exp Anim Sci     | (p\<0.05).            |
| 0.2%, and 1%       | 42:160-170.             | Significant           |
|                    |                         | reductions in         |
|                    | **Open Literature**     | horizontal movements  |
|                    |                         | (crossed quadrants)   |
|                    | Male and Female LEW.1K  | were observed at all  |
|                    | Rat                     | dose levels and were  |
|                    |                         | characterized by a    |
|                    | Malek et al. (2003a):   | U-shaped dose         |
|                    | Rats were exposed to 0, | response. The lowest  |
|                    | 1.0, 2.5, or 5.0 ppm    | dose tested (1 ppm)   |
|                    | (0, 1.23, 3.08, or 6.15 | demonstrated higher   |
|                    | mg/m^3^) formaldehyde   | level of activity     |
|                    | for 2 hours. Mean       | suppression than the  |
|                    | formaldehyde levels of  | two higher doses, but |
|                    | 1.01 ± 0.29 ppm, 2.51   | all groups were still |
|                    | ppm (standard deviation | suppressed relative   |
|                    | is missing) and 5.04 ±  | to controls. Although |
|                    | 0.27 ppm were achieved. | female rats displayed |
|                    | Locomotor activity was  | a greater level of    |
|                    | assessed for 1 hour in  | activity overall, a   |
|                    | an open field 2 and 24  | similar U-shaped      |
|                    | hours after termination | dose-response pattern |
|                    | of formaldehyde         | was also observed.    |
|                    | exposure.               |                       |
|                    |                         | After 24 hours, as    |
|                    | Malek et al. (2003b):   | expected, controls    |
|                    | Rats (10 per group)     | demonstrated          |
|                    | were exposed at 0, 0.1, | habituation to the    |
|                    | 0.5, or 5.0 ppm (0,     | test apparatus        |
|                    | 0.123, 0.615, or 6.15   | exhibiting only 20%   |
|                    | mg/m^3^) formaldehyde   | of the motor activity |
|                    | for 2 hours. Open field | observed on day 1. In |
|                    | behavior tests were     | contrast,             |
|                    | conducted on each       | formaldehyde-treated  |
|                    | animal 2 hours after    | animals failed to     |
|                    | formaldehyde exposure.  | demonstrate the same  |
|                    |                         | degree of             |
|                    |                         | habituation. Activity |
|                    |                         | levels for males      |
|                    |                         | observed on day 2     |
|                    |                         | were 60-80% of the    |
|                    |                         | activity levels seen  |
|                    |                         | on day 1.             |
|                    |                         | Formaldehyde-treated  |
|                    |                         | females also failed   |
|                    |                         | to habituate and      |
|                    |                         | actually demonstrated |
|                    |                         | increases in activity |
|                    |                         | on day 2 relative to  |
|                    |                         | day 1 at all          |
|                    |                         | formaldehyde exposure |
|                    |                         | levels.               |
|                    |                         |                       |
|                    |                         | Malek et al. (2003b): |
|                    |                         |                       |
|                    |                         | **LOAEL (M) = 0.1     |
|                    |                         | ppm, 2 hours**        |
|                    |                         |                       |
|                    |                         | The number of crossed |
|                    |                         | quadrants for both    |
|                    |                         | controls and a 5 ppm  |
|                    |                         | group are comparable  |
|                    |                         | to those observed in  |
|                    |                         | the first study.      |
|                    |                         | Horizontal movement   |
|                    |                         | was decreased by      |
|                    |                         | formaldehyde exposure |
|                    |                         | in a dose dependent   |
|                    |                         | manner with           |
|                    |                         | significant           |
|                    |                         | reductions in motor   |
|                    |                         | activity as low as    |
|                    |                         | 0.1 ppm in males and  |
|                    |                         | 0.5 ppm in females.   |
|                    |                         | The consistency of    |
|                    |                         | the data across       |
|                    |                         | studies and between   |
|                    |                         | genders provides      |
|                    |                         | greater confidence in |
|                    |                         | the effects of low    |
|                    |                         | level formaldehyde    |
|                    |                         | exposure on this      |
|                    |                         | standard test of      |
|                    |                         | neurotoxicity.        |
+--------------------+-------------------------+-----------------------+
| 870.6500           | []{.mark}               | **LOAEL: 2.6 ppm, 10  |
|                    |                         | min/90 days**         |
| S                  | Pitten, FA; Kramer, A;  |                       |
| chedule-controlled | Herrmann, K; et al.     | The authors reported  |
| operant behavior   | (2000) Formaldehyde     | that no gender        |
|                    | neurotoxicity in animal | differences existed   |
| Purity: Not        | experiments. Pathol Res | as a function of      |
| reported           | Pract 196:193-198.      | formaldehyde          |
|                    |                         | treatment; therefore, |
|                    | **Open Literature**     | data were presented   |
|                    |                         | by combining sexes.   |
|                    | Adult Male and Female   | Control rats showed   |
|                    | Wistar Rat (5 to        | no change in error    |
|                    | 8/sex/group)            | rate but a slight     |
|                    |                         | decrease in running   |
|                    | Pitten et al. (2000)    | time through the maze |
|                    | evaluated the effects   | during the course of  |
|                    | of very brief           | the experiment. The   |
|                    | formaldehyde exposures  | formaldehyde-exposed  |
|                    | (10 minutes) but        | groups began with a   |
|                    | prolonged duration (90  | similar performance   |
|                    | days) on previously     | level and error rate  |
|                    | learned performance in  | as controls, but      |
|                    | a land version of the   | their performance     |
|                    | labyrinth maze. Rats    | degraded over the     |
|                    | were acclimated to the  | course of             |
|                    | task for 14 days, 2     | formaldehyde          |
|                    | trials/day. Animals     | exposure. By the      |
|                    | were required to make a | fourth week of        |
|                    | series of five          | exposure, increased   |
|                    | consecutive turns from  | numbers of errors     |
|                    | the entrance of the     | were evident in both  |
|                    | maze to retrieve a      | exposed groups        |
|                    | piece of cheese placed  | relative to controls. |
|                    | in the goal box at the  | This trend reached    |
|                    | opposite end. Animals   | statistical           |
|                    | were exposed to 0 ppm,  | significance by the   |
|                    | 2.6 ppm (0.25%          | thirteenth week for a |
|                    | formaldehyde solution   | greater than twofold  |
|                    | to yield 3.06 ± 0.77    | increase in error     |
|                    | mg/m3 ), or 4.6 ppm     | rate (p\<0.05).       |
|                    | (0.70% formaldehyde     | Formaldehyde-treated  |
|                    | solution to yield 5.55  | rats also tended to   |
|                    | ± 1.27 mg/m3)           | have increased run    |
|                    | formaldehyde, 10        | times through the     |
|                    | minutes/day, 7          | maze (p=0.04), but no |
|                    | days/week for 90 days.  | difference was seen   |
|                    | Animals were assessed   | by formaldehyde       |
|                    | for performance in the  | concentration. By 4   |
|                    | maze every seventh day, | weeks after           |
|                    | at least 22 hours after | termination of        |
|                    | the exposure on the     | exposure, no          |
|                    | previous day. At the    | statistical           |
|                    | end of the 90-day       | differences among the |
|                    | exposure period,        | three groups were     |
|                    | monitoring of maze      | evident, but the      |
|                    | performance continued   | tendency for the two  |
|                    | once every 10 days for  | exposed groups to     |
|                    | an additional 40 days.  | make more errors and  |
|                    |                         | have longer latencies |
|                    |                         | remained. Since       |
|                    |                         | Pitten et al. (2000)  |
|                    |                         | tested animals after  |
|                    |                         | the task was          |
|                    |                         | acquired, these       |
|                    |                         | results indicate      |
|                    |                         | deficits in the       |
|                    |                         | retention of a        |
|                    |                         | previously learned    |
|                    |                         | task.                 |
+--------------------+-------------------------+-----------------------+
| Other              | Boja JW, Nielsen JA,    | Exposure to 6.20      |
|                    | Foldvary E, et al.      | mg/m^3^ formaldehyde  |
| Purity: 96%        | (1985) Acute Low-Level  | resulted in           |
|                    | Formaldehyde            | statistically         |
|                    | Behavioural and         | significant decreased |
|                    | Neurochemical Toxicity  | motor activity within |
|                    | in the Rat. Prog        | 15 minutes. At the    |
|                    | Neuro-Psychopharmacol   | beginning of day 2,   |
|                    | Biol Psychiat           | all of the rats       |
|                    | 9:671-674.              | exposed to            |
|                    |                         | formaldehyde on day 1 |
|                    | **Open Literature**     | displayed lower       |
|                    |                         | activity levels.      |
|                    | 88 M Sprague-Dawley Rat | Similar effects on    |
|                    |                         | motor activity were   |
|                    | Rats were exposed to    | seen at the 12.39     |
|                    | either air or           | mg/m^3^ formaldehyde  |
|                    | formaldehyde at         | exposure level,       |
|                    | concentrations of 5,    | whereas effects seen  |
|                    | 10, or 20 ppm (6.20,    | after 24.79 mg/m^3^   |
|                    | 12.39, or 24.79         | exposure were         |
|                    | mg/m^3^) via inhalation | reported to be "not   |
|                    | for 3 hours on two days | readily               |
|                    |                         | interpretable" and    |
|                    |                         | were not shown.       |
|                    |                         | 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           | []{.mark}               | DNA-protein           |
|                    |                         | crosslinking occurred |
| General Metabolism | Casanova, Mercedes,     | at all                |
|                    | Donald F. Deyom and     | concentrations. The   |
|                    | Henry D\'A. Heck (1989) | formation of          |
|                    | Covalent Binding of     | crosslinks was        |
|                    | Inhaled Formaldehyde to | interpreted in terms  |
|                    | DNA in the Nasal Mucosa | of a nonlinear        |
|                    | of Fischer 344 Rats:    | pharmacokinetic model |
|                    | Analysis of             | incorporating         |
|                    | Formaldehyde and DNA by | oxidation of inhaled  |
|                    | High-Performance Liquid | formaldehyde as a     |
|                    | Chromatography and      | defense mechanism.    |
|                    | Provisional             | The slope of the      |
|                    | Pharmacokinetic         | fitted                |
|                    | Interpretation.         | c                     |
|                    | Fundamental and Applied | oncentration-response |
|                    | Toxicology 12: 397-417. | curve at 12 mg/m^3^   |
|                    |                         | is7.3-fold greater    |
|                    | **Open Literature**     | than at 0.37 mg/m^3^, |
|                    |                         | and the               |
|                    | Rat (4/group),          | detoxification        |
|                    | nose-only exposure      | pathway is            |
|                    |                         | half-saturated at an  |
|                    | 0, 0.3, 0.7, 2, 6, or   | airborne              |
|                    | 10 ppm (0.37, 0.87,     | concentration of 3.2  |
|                    | 2.5, 7.4, or 12         | mg/m^3^.              |
|                    | mg/m^3^) for 6 hours    |                       |
+--------------------+-------------------------+-----------------------+
| 870.7485           | []{.mark}               | The major route of    |
|                    |                         | nucleic acid labeling |
| General Metabolism | Casanova-Schmitz,       | at all concentrations |
|                    | Mercedes, Thomas B.     | and in all tissues    |
|                    | Starr, and Henry D\'A.  | was metabolic         |
|                    | Heck (1984)             | incorporation;        |
|                    | Differentiation between | protein labeling in   |
|                    | Metabolic Incorporation | the respiratory       |
|                    | and Covalent Binding in | mucosa was mainly due |
|                    | the Labeling of         | to covalent binding   |
|                    | Macromolecules in the   | at the higher         |
|                    | Rat Nasal Mucosa and    | formaldehyde          |
|                    | Bone Marrow by Inhaled  | concentration.        |
|                    | (14C)- and (3H)         | Incorporation of 14C- |
|                    | Formaldehyde.           | formaldehyde into DNA |
|                    | Toxicology and Applied  | in the respiratory    |
|                    | Pharmacology 76: 26-44. | mucosa was maximal at |
|                    |                         | 7.4 mg/m^3^ but       |
|                    | **Open Literature**     | decreased at higher   |
|                    |                         | concentrations,       |
|                    | Rats (4/group)          | whereas labeling of   |
|                    |                         | DNA in the olfactory  |
|                    | 14C and 3H-             | mucosa and bone       |
|                    | formaldehyde was        | marrow increased      |
|                    | administered at doses   | monotonically with    |
|                    | of 0, 0.3, 2, 6, 10, or | concentration.        |
|                    | 15 ppm (0, 0.37, 2.5,   | Evidence for covalent |
|                    | 7.4, 12, or 19 mg/m^3^) | binding of            |
|                    | for 6 hours             | formaldehyde 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.             |
+--------------------+-------------------------+-----------------------+

**9.0 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; submitted by Hallemite Lehn & Fink, Montvale, N.J.; CDL:
> 229296-A)
>
> **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.
> Toxicology and Applied Pharmacology 16: 646-655. (NCEA)

[]{.mark}

> **00082136** Schnurer, L.B. (1963) Maternal and foetal responses to
> chronic stress in pregnancy: A study in albino rats. Acta
> Endocrinologica, Supplement 80 ?:3-96. (Also in unpublished submission
> received Oct 15, 1973 under 4G1438; submitted by Chevron Chemical Co.,
> 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:
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