listed species (U.S. EPA 2004). If any of the Listed Species LOC
Criteria are exceeded for either direct or indirect effects in the
Agency’s screening-level risk assessment, the Agency identifies any
listed or candidate species that may occur spatially and temporally in
the footprint of the proposed use. Further biological assessment is
undertaken to refine the risk. The extent to which any species may be at
risk determines the need to develop a more comprehensive consultation
package as required by the ESA.

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

10.0	INCIDENT REPORTS

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

(1) OPP Incident Data System (IDS

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

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

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

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

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

No incidences were reported in the Poison Control Center Data.

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

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

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APPENDIX A – Physical and Chemical Properties of

Formaldehyde and Paraformaldehyde

Table A1.  Physical/Chemical Properties for Formaldehyde and
Paraformaldehyde

Parameter	Formaldehyde	Paraformaldehyde

Molecular Weight	30.03 (Gas)

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

Color	Clear Colorless (54% soln.)

Clear Colorless (37% soln.)

Colorless (Gas)	White prill

White crystalline solid

White solid flakes

Physical State	Liquid (54% solution)

Liquid (37% solution)

Gas	Solid, flakes, Powder

Odor	Pungent (54% solution)

Pungent (37% solution)

Pungent, suffocating  irritating odor (Gas)	Pungent formaldehyde odor

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

N/A (Gas at room temperature)

-92ºC (Gas)	120 to 170ºC closed tube

Boiling Point	~100ºC (54% solution)

101ºC (214ºF) (37% soln.)

-19.5ºC (-3ºF) – (Gas)

-21ºC (Gas)	Solid at ambient temperature

Slowly sublimes to formaldehyde gas.

760 mm Hg

Sublimes at 150ºC

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

Sp gr. 1.067 – 54% soln

8.75 to 9 lbs/gal – 37% soln

Sp gr. 1.05 at 75ºF – 37% soln

Sp gr. 1.08 at 20ºC – 37% soln

0.8153 gm/cm3 @ 20ºC (Gas)

0.815 g/mL at 20ºC (Gas)

1•kg·m-3 (Gas)	750 to 850 kg/m3

Density: 1.46 g/ml @ 15ºC

Density varies with particle size and degree of compaction.

Free flowing: approx. 37 lbs/cu ft

Packed: approx.  42 lbs/cu ft

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

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

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

Dilute Alkali: Very Soluble

Dilute Acid: Very Soluble

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

Solubility (Room Temperature):

• Ethanol 2.37%

• Methanol 4.71%

• Hexane 5.10 ppm

• Ether 108 ppm

• 1.0 N NaOH 22.9%

• 0.1N NaOH 22.8%

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

Slightly soluble in cold water.

Difficulty Soluble.

Partial – dependent on pH, temperature and molecular weight.

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

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

Vapor Pressure

Vapor Density	40 mmHg 30ºC – 54% soln

40 mmHg 30ºC – 37% soln

1 mm Hg /Formalin (TOXNET)

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

3,890 mm Hg @ 25ºC (Gas) (TOXNET)

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

1 mm Hg @ 30ºC

1.4 mm Hg @25ºC

1.55 mm Hg

@30ºC mm Hg Dry Air 1; Dew point 3

@60ºC mm Hg Dry Air 5; Dew point 15

10.5 mm Hg @ 25ºC (TOXNET)

1.03 (Air=1)

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

37% soln.:

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

1.8 X 1OE-4 for formic acid.

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

1.8 x l0E-4 for formic acid

pKa = 15.50 @ 25ºC (TOXNET)

Partition coefficient

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

-0.65 (calculated)

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

pH	5.5 – 6.2  (54% soln)

5.83 (54% soln)

3.5 – 4.5 (37% soln)

4 to 5 (37% soln)

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

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

Stability to normal and elevated temperatures.

Stability to metals.

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

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

In excess of 2 years (37% soln)

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

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

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

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

High temperature causes liberation of formaldehyde gas.

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

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

~100ºF (54%)

Flash Pt. 134ºF

Flash point: 122ºF (37% soln)

>140ºF – 37% soln

Flashpoint 60ºC (Gas)

Flammability limits at 25ºC 7–73%

Autoignition temperature 300ºC

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

Flash point: 70°C

158F Tag Closed Cup (TCC)

200F Tag Open Cup (TOC)

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

158F Tag Closed Cup (TCC)

200F Tag Open Cup (TOC)

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

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

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

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

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

37% Soln:

Lower Explosion Limit: 7 %

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

Explosion limits: 7.0 – 73%

Autoignition temp: 300ºC (572ºF)

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

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

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

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

Aqueous formaldehyde is corrosive to carbon steel (TOXNET)

Corrosive to metal (Gas)	Moderate

Dielectric Breakdown Voltage	45e @20ºC

N/A	~450e @20ºC

Oxidation/Reduction: Chemical Incompatibility	Oxidation:

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

HCHO + ½ O2 > HCOOH

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

2HCHO + O2 > 2CO + 2H2O

Reduction:

HCHO + H2 < > CH3OH

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

.

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

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

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

HCH0+1/2 O2 > HCOOH

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

2HCHO +02 > 2C0 + 2H20

Reduction:

HCHO + H2 < > CH3OH

Incompatibility:

Incompatible with strong acids, organic acids, strong oxidizing

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

Incompatibilities:

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

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

Hazardous Polymerization:

Will not occur.

APPENDIX B - Toxicity Profile for Formaldehyde and Paraformaldehyde

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

Guideline Number/

Study Type/

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

Citation/ Classification/ Doses	Results

Subchronic Toxicity

870.3100

90-Day oral toxicity in rodents

Purity: 37% a.i.

	MRID 00124677

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

Not Reviewed

10 male Holtzman rats/dose

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

	NOAEL:  0.3% formaldehyde

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

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

870.3100

28-Day oral toxicity in rodents

Purity: 60% a.i.

	MRID 00134114

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

Not Reviewed

10 Male Sprague-Dawley rats/dose

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

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

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

870.3100

90-Day oral toxicity in rodents

Purity: 95% a.i., aqueous paraformaldehyde

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

Open Literature

Sprague-Dawley Albino Rat

(15/sex/dose)

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

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

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

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

870.3100

28-Day oral toxicity in rodents

Paraformaldehyde (95% a.i., aqueous)

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

Open Literature

Rat (10/sex/dose)

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

	NOAEL= 25 mg/kg/day

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

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

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

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

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

870.3150

90-Day oral toxicity in nonrodents

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

Open Literature

Beagle Dog (4/sex/dose)

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

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

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

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

870.3465

90-Day inhalation toxicity

	MRID 00082134

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

Not Reviewed

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

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

870.3465

6-Week inhalation toxicity

Purity = 4.96%

	MRID 00149755

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

Core-Supplementary

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

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

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

Body weight

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

Organ weight

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

Gross and Microscopic Pathology

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

870.3465

90-Day inhalation toxicity

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

Open Literature

Rats (10/sex/dose)

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

	NOAEL: 1.2 mg/m3

LOAEL: 12 mg/m3

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

870.3465

90-Day inhalation toxicity

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

Open Literature

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

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

	NOAEL = 1.24 mg/m3

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

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

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

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

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

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

870.3465

90-Day inhalation toxicity

Purity = ???

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

20 Mice and Rats

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

	NOAEL = 4 ppm (LDT)

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

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

870.3465

90-Day inhalation toxicity

Purity = ???

	– citation not provided in memo

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

25 Rats

	Systemic NOAEL = 0.028 ppm

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

ChE NOAEL = 0.82 ppm

ChE LOAEL = 2.4 ppm

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

870.3465

90-Day inhalation toxicity

Purity: Not Reported

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

Open Literature

25 rats

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

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

Developmental Toxicity

870.3700a

Prenatal Developmental Toxicity

Purity: 35% a.i.

	MRID 00082136, 00123770

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

Not Reviewed

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

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

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

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

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

870.3700a

Prenatal

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

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

Not Reviewed

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

Pregnant White Rat – No Information on Number and Type provided

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

870.3700a

Prenatal

Developmental

Toxicity (rodent)

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

	MRID 00164652

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

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

Female CD-1 Mice

	Maternal Toxicity:

NOAEL = 0 mg/kg/day

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

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

870.3700a

Prenatal

Developmental

Toxicity

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

Open Literature

Female Sprague-Dawley rats (25/dose)

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

	Maternal Toxicity:

NOAEL = 24.8 mg/m3

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

Offspring Toxicity:

NOAEL = 12.4 mg/m3

LOAEL = 24.8 mg/m3, based on reduced fetal

weight gain

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

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

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

870.3700a

Prenatal

Developmental

Toxicity (rodent)

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

Open Literature

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

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

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

Reproductive Toxicity

870.3800

Reproduction and fertility effects

Purity: 40% a.i.

	MRID 00143291

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

51 female Beagle dogs

0, 3.1, or 9.4 mg/kg/day

Not Reviewed

	The study revealed no teratogenic action.

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

870.3800

Reproduction and fertility effects

Purity: 40% a.i.

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

Open Literature

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

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

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

Chronic Toxicity

870.4100a

Chronic Toxicity

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

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

Open Literature

B6C3F1 Mouse (5/sex/group)

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

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

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

870.4100a

Chronic Toxicity

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

Open Literature

Male Fischer 344 rats (32/dose)

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

	NOAEL: 0.4 mg/m3

LOAEL: 2.5 mg/m3

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

Carcinogenicity

870.4200a

Oncogenicity (Rat)

	MRID 00143288

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

Rat

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

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

870.4200a

Oncogenicity (Rat)

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

Open Literature

32 Male Fischer 344 rats/dose

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

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

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

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

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

870.4200a

Oncogenicity (Rat)

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

Open Literature

Male Wistar rats

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

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

870.4200b

Oncogenicity

(Mouse)

Purity: 1% and 10%

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

Open Literature

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

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

870.4200b

Oncogenicity

(Mouse)

Purity: 10%

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

Open Literature

Female CD-1 Mouse

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

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

870.4200b

Oncogenicity

(Mouse)

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

Open Literature

Female Sencar Mice (30/group)

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

870.4200

Oncogenicity

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

Open Literature

88 male Syrian golden hamsters

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

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

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

870.4300

Chronic/ Oncogenicity

 	MRID 00143289

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

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

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

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

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

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

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

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

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

Neurotoxicity

870.6200

Neurotoxicity screening battery

Purity:

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

(2003b) – 0.1%, 0.2%, and 1%

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

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

Open Literature

Male and Female LEW.1K Rat

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

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

Malek et al. (2003a):

LOAEL = 1.0 ppm, 2 hours

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

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

Malek et al. (2003b):

LOAEL (M) = 0.1 ppm, 2 hours

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

870.6500

Schedule-controlled operant behavior

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

Open Literature

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

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

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

Other

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

Open Literature

88 M Sprague-Dawley Rat

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

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

Metabolism

870.7485

General Metabolism

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

Open Literature

Rat (4/group), nose-only exposure

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

870.7485

General Metabolism

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

Open Literature

Rats (4/group)

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

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

Special Studies

Modeling

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

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

Open Literature

3-D F344 Rat Model

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

Sensitization

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

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

Open Literature

18 F344 and 18 Brown Norway (BN) Rats

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

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

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

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

Sensitization

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

Open Literature

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

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

Sensitization

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

Open Literature

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

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

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

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

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

Pulmonary Hypersensitivity

	MRID 43167201

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

Minimum

Guinea Pig (8/group)

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

870.1300

Acute Inhalation Toxicity

Purity: 95%

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

Open Literature

255 Female (SPF) B6C3F1 Mice

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

Inhalation

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

Open Literature

9 Male Rhesus Monkey (Macaca mulatta)

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

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

Inhalation

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

Open Literature

Male F-344 (CDF/ CrIBR) rats

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

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

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

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

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

Inhalation

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

Open Literature

Rat

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

	NOAEL: 2.5 mg/m3

LOAEL: 7.4 mg/m3

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

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

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

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

Inhalation Short and Intermediate term

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

Open Literature

Rats (36/group)

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

	NOAEL: 2.5 mg/m3

LOAEL: 7.4 mg/m3

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

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

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

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

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

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

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

Other – Sensory Irritation

Purity: 37%

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

Open Literature

M SPF Swiss Webster Mouse (4/group)

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

exposure (as predicted by the

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

Other - Sensory Irritation

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

Open Literature

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

10 minute head-only exposure to formaldehyde and other aldehydes

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

RD50: 4.90 ppm (3.9–6.4 ppm) (B6C3F1)

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

870.1300

Other - Sensory Irritation

Purity: 5%

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

Open Literature

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

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

	RD50: 13.8 ppm

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

870.1300

Other - Sensory Irritation

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

Open Literature

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

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

870.1300

Other - Sensory Irritation

Purity: 90%-92% Paraformaldehyde

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

Open Literature

M Wistar rats (4/dose)

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

870.1300

Other - Sensory Irritation

Purity: 95% Paraformaldehyde

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

Open Literature

Adult M Sprague-Dawley rats (5/experiment)

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

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

There was a progressive depression in response to amyl alcohol with
increasing stimulus of formaldehyde concentration [p < 0.01, analysis of
variance (ANOVA)]. The effects of exposure to 2.0 ppm were similar
regardless of whether it was presented immediately as a separate
exposure or as the final concentration of a progressively increasing