DRAFT
INFORMAL GUIDANCE LEVEL FOR FORMALDEHYDE
August 27, 1982
Background
The Office of Drinking Water provides advice on health
effects upon request, concerning unregulated contaminants
found in drinking water supplies. This information suggests
the level of a contaminant in drinking water at which adverse
health effects would not be anticipated. A margin of safety
is factored in so as to protect the most sensitive members
of the general population. This guidance is not a legally
enforceable standard.
General Information and Properties
Formaldehyde is characterized by the following properties:
colorless gas; molecular weight 30, melting point -92° C;
boiling point -19° C; vapor pressure -88 at 10 mm Hg; specific
gravity 0.815 at 4° C. In aqueous solution, formaldehyde
undergoes hydration to yield the monohydrate and polymeric
hydrates. The distribution of formaldehyde, as the monomer and
polymer, is dependent on the concentration, age, and tempera-
ture of the formaldehyde solution (Verschueren, 1977).
The odor threshold of formaldehyde in water has been
reported to be 20 mg/liter (Nazarenko, 1960) or 49.9 mg/liter
(Baker, 1963).
The American Conference of Governmental Industrial
Hygienists (ACGIH, 1974) recommends a threshold limit value
(TLV) for formaldehyde of 2 ppm. The present Occupational
Safety and Health Administration (OSHA) federal workplace
standard for formaldehyde is 3 ppm, as a time-weighted average
concentration over an 8-hour workshift (1979).
The stability of formaldehyde in distilled water, tap
water, and tap water spiked with soil extract is summarized
in a Russian article focusing on allowable concentrations of
formaldehyde in water basins (Nazarenko, 1960). The stability
of formaldehyde in various water samples was assessed by measur-
ing formaldehyde concentration on days 1, 2, 3, 4 and 5, respec-
tively. The formaldehyde concentrations in various water
samples were as follows:
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Formaldehyde (mgi) in Water
Experimental
Conditions
Original
Determ
ination
Time
First
Day
Second
Day
Third
Day
Fourth
Day
Fifth
Day
Distilled Water
4.5
4.5
4.5
4.5
4.5
4.4
Tap Water
Tap Water + 1 mg/i
5.0
5.0
4.7
4.5
4.5
4.3
4.0
3.7
3.5
3.0
2.7
1.5
soil extract
Tap Water + 5 mg/i
5.0
4.3
3.0
NONE
soil extract
The above data show that the formaldehyde concentrations
in distilled water remained constant for 5 days and that the
rate of formaldehyde concentration abatement in water was
highly dependent upon the presence of the relative concentra-
tion of microorganisms.
Pharmacokinetics
Formaldehyde enters the body via ingestion, inhalation,
dermal absorption or ocular contact. The metabolic fate of
formaldehyde has been studies in dogs following oral or
intravenous administration of formaldehyde (Malorny et al.
1965). In one phase of the study, dogs were administered at
0.6 percent formaldehyde solution orally by intubation (70
mg/kg body weight). The principal metabolite, formic acid,
was detected in the plasma at a level of 7.1 mg percent 20
minutes after dosing and a level of 12.9 mg percent 2 hours
after dosing. However, formaldehyde was not detected in the
plasma. In another set of experiments, dogs were administered
a 0.2M formaldehyde solution intravenously (35 mg/kg body
weight). During infusion, the level of formaldehyde in the
plasma was 0.95 mg percent while in red blood cells, the level
was 4.06 mg percent. One hour following infusion, formaldehyde
was no longer detectable in plasma although trace levels were
found in erythroctyes (0.2 mg percent). The maximum concentra-
tion of formic acid in plasma was 14.4 mg percent after 1 hour,
suggesting a rapid transformation of formaldehyde to formic
acid. Furthermore, the investigators stated that the biolog-
ical half-life for formic acid was 90 minutes.
The metabolic fate of l 4 C-formaldehyde in rats has been
studied following intraperitoneal administration (Neely , 1964).
Adult female rats were given approximately 70 mg/kg of i4c-
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formaldehyde. The investigator reported the following findings:
(a) 82 percent of the formaldehyde dose was detected in the
expired air as ^CO?; (b) urine contained about 14 percent of
the isotope in the form of methionine, serine, and an adduct
formed from cysteine and formaldehyde, accounting for 96 per-
cent in 48 hours.
The animal studies in rats by Neely (1964) suggest that
the absorption of formaldehyde is approximately 100 percent of
the formaldehyde dose when administered intraperitoneally.
Therefore, in the development of the guidance level for formal-
dehyde, it will be assumed that 100 percent of formaldehyde
will be absorbed by the exposed individual.
Summary of Toxicity Information
The acute toxicity of formaldehyde from different expo-
sure routes has been determined for the following mammalian
species:
Rats, oral LD5Q = 800 mg/kg; subcutaneous LD5Q =
400 mg/kg; inhalation LD50 = 1 rag/liter (1.0 mg/m^)
(Smyth et al. 1941; Skog, 1950).
0 Guinea Pigs, oral LD5Q = 260 mg/kg (Smyth et al. 1941).
w Mice, subcutaneous LD5Q = 300 mg/kg (Skog, 1950).
Although a large body of information on the toxic effects
in humans and animals from the inhalation of formaldehyde
exists, the information concerning effects from oral administra-
tion of formaldehyde is very limited.
A study of possible toxic effects of prolonged formalde-
hyde ingestion was reported by Yonkman et al. (1941). Two
human subjects were placed on a daily consumption of "pure"
formaldehyde in water for 13 weeks. The subjects initially
received 22 mg of formaldehyde per day for the first 14 days.
Thereafter the daily dosage of formaldehyde was increased
every 7 or 14 days until dosage had reached 200 mg per day by
the 13th (final) week. Blood samples were analyzed periodic-
ally for hemoglobin content, red or white cell counts and
morphology. Urine samples were analyzed for the presence of
formaldehyde and albumin. There were no changes in hemoglobin,
in the number of red and white blood cells or in cell morph-
ology. Urine analyses were negative for free formaldehyde and
albumin. However, the subjects experienced mild pharyngeal
and gastric discomfort, but this was alleviated when the for-
maldehyde dosage was diluted in water by twice the initial
concentration.
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The results of other formaldehyde ingestion studies in
animals were summarized in a Russian review article on allow-
able concentrations of formaldehyde in water basins (Nazarenko,
1960). Dogs and rabbits were administered formaldehyde diluted
in water and milk at daily doses of 2-100 mg/kg for up to 129
days. Deaths were reported in dogs given as little as 2 mg/kg
for 50 days. Rabbits were less sensitive; only one died that
received 50-100 mg/kg. No effects were observed on hematology,
weight gain, or fertility in rats administered formaldehyde by
stomach tube at 6-8 mg/kg for 124 days. In another experiment,
only slight, inconsistent effects on conditioned reflexes were
observed in rats given formaldehyde in the drinking water at
0.5-20 mg/i for 71-118 days. Formaldehyde administered to rats
in the drinking water at 1, 5, and 20 mg/i for ii weeks caused
no histologic changes. However, when the dose was increased to
100 rng/l for an additional unspecified period, there were histo-
logic changes in the liver and spleen.
Carcinogenicity
Some experimental data are available which implicate for-
maldehyde as a potential carcinogen. Horton et al. (1963)
exposed mice via inhalation to formaldehyde vapor at concentra-
tion of 50, 100, and 200 mg/rn 3 for 1 hour three times a week
for up to 35 weeks. Formaldehyde exposure was continued after
the 35th week for the 50 mg/rn 3 group at a level of 150 mg/rn 3
for an additional 29 weeks. Histopathologic analysis of the
animals exposed to formaldehyde levels of 50 or 100 mg/in 3
revealed basal cell hyperplasia and stratification of the
epithelium of the trachea and bronchi at exposure levels of
100 mg/rn 3 , squamous cell metaplasia was evident. However,
there was no evidence of pulmonary neoplasrns in mice exposed
to formaldehyde vapor at concentration of 50 mg/rn 3 for 35 weeks
followed by exposure to 150 mg/rn 3 for 29 weeks. lonescu et al.
(1978) detected bronchial cell hyperplasia and squamous cell
metaplasia in rabbits exposed to formaldehyde vapor (3 percent;
10 g/m 3 ) for 3 hours daily for up to 50 days. No squamous cell
carcinomas were noted.
In contrast, Swenberg et al. (1980) reported the occur-
rence of squamous cell carcinomas of the rat nasal cavity after
inhalation exposure to formaldehyde. In the above study,
Fischer rats were exposed via inhalation to formaldehyde vapor
at concentrations of 2.5 mg/rn 3 (2 ppm), 7.5 mg/rn 3 (6 ppm) or
18.7 mg/rn 3 (15 ppm), 6 hours/day, 5 days/week, for 18 months
of a 24-month study. Histologic examination of the rats re-
vealed a high incidence (18 percent) of neoplasms of the nasal
cavities in animals from the 15 ppm exposure group killed at
18 months. Histologic examination of tissues from rats ex-
posed to 15 ppm killed after 6 and 12 months of exposure in-
dicated that formaldehyde-induced lesions (epithelial dysplasia,
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squamous metaplasia) were limited to the nasal cavities.
Epithelial dysplasia and squamous metaplasia also occurred in
animals from the 2, and 6 -ppm exposure groups; however, no
squamous cell carcinomas were observed.
Mutagenicity
Formaldehyde produces genetic damage in several micro-
organisms such as Escherichia coil, Salmonella typhimurium ,
and Saccharomyces cerevisiae . Formaldehyde is weakly muta-
genie as observed in bacterial tests: S. typhimurium (Sasaki
and Endo, 1978) and E. coil (Nishioka, 1973). Formaldehyde is
known to induce DNA-protein cross-links in bacteria CE. coil )
(Wilkins and Macleod, 1976) and in yeast (S. cerevisiae )
(Magana-Schwencke and Ekert, 1978). Formaldehyde-induced
mitotic recombination has also been reported (Chanet et al.
1975).
Reproductive and Teratogenic Effects
Based on the currently available data from animal studies,
formaldehyde does not appear to have an adverse effect on repro-
ductive processes, embryonic and fetal development, or organo-
genesis. 1-lurni and Ohder (1973) reported no adverse reproduc-
tive effects in beagle dogs exposed to formaldehyde. In the
above study, dogs were fed diets containing 125 ppm (3.1 mg/kg!
day) or 375 ppm (9.4 mg/kg/day) of formaldehyde on days 4-56 of
gestation. No adverse reproductive effects were noted in the
formaldehyde-treated group as assessed by the following para-
meters: pregnancy rate, length of gestation, litter size,
growth retardation and survival to weaning. Further, no
visceral or skeletal malformations were noted in the progeny
of the formaldehyde exposed group. Marks et al. (1980)
assessed the effect of formaldehyde on reproduction in mice.
In the above study, pregnant albino mice were given formalde-
hyde by gavage at dose levels of 74, 148, or 185 mg/kg/day on
days 6-15 of gestation. At the highest dose (185 mg/kg/day)
of formaldehyde, 22 of the 34 pregnant mice died before the
18th day, whereas the 74 and 148 mg/kg/day doses had no signi-
ficant effect on the pregnant dams. Formaldehyde had no
adverse effects on reproductive performance in mice as asses-
sed by the following parameters: number of implants, number
of resorptions, fetal deaths and fetal weight. At all dose
levels, formaldehyde had no significant effect on the incidence
of malformed fetuses. The authors concluded that formaldehyde
is not teratogenic to the albino mouse.
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Cardiovascular Effects
The effects of formaldehyde on the cardiovascular system
of rats have been reported by several investigators (Egie and
Hudgins, 1974). Egle and Hudgins investigated the effects of
intravenous infusion (0.5, 1.0, 5.0, 10.0, 20 mg/kg) and inhala-
tion exposure [ 2 mg/mi (2 g/m 3 )) of formaldehyde on blood pres-
sure and heart rate in the male Wistar rat. Formaldehyde was
also given to rats with altered sympathetic function (pretreat-
ment with phentolamine, an adrenergic blocker or reserpine
pretreatment with subsequent adrenalectorny) as well as to
atropinized and vagatomized rats. The effects of formaldehyde
on blood pressure were as follows: a dose of 0.5 mg/kg caused
an increase in blood pressure within 5 second after injection;
a dose of 1.0 mg/kg in most instances produced an increase in
blood pressure, in some instances depressor responses were
noted; at the higher levels (> 5 mg/kg) only depressor effects
were noted, which was also associated with bradycardia. In
rats pretreated with reserpine followed by adrenalectomy, the
pressor effects of formaldehyde were less frequent. Further-
more, pretreatment with phentolamine resulted in decreased
pressor effects of formaldehyde. The effect of formaldehyde
on the heart rate < 20 mg/kg did not alter heart rate signi-
ficantly; however, a pronounced decrease in heart rate was
observed after dosing with 20 mg/kg. In addition, the cardio-
inhibitory effect of formaldehyde was markedly decreased by
atropine pretreatment and abolished by vagotomy.
Skin Irritation and Sensitization
Primary skin irritation and allergic contact dermatitis
from formaldehyde is quite common. Allergic contact dermatitis
can be caused by contact with formaldehyde, formalin, formalde-
hyde-releasing agents used in cosmetics, medications, germi-
cides and decomposition of formaldehyde-containing resins.
Phillips et al. (1972) studies the dermal response of rabbit
and human skin to formaldehyde (10 percent w/v, water) using
a variation of the standard Draize rabbit irritancy test.
Jordan et al. (1979) examined the formaldehyde threshold re-
sponse in formaldehyde allergic subjects by applying 0, 30, 60,
or 100 ppm of formaldehyde in a methanol-water vehicle for 1
week. The closed patch test method resulted in a response to
30 ppm.
Guidance Development
Currently available animal and human data suggest that
the physiological and/or biochemical changes in the cardio-
vascular and gastrointestinal tract following formaldehyde
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exposure are primary indicators of formaldehyde toxicity.
Acceptable dose-response ingestion data are not available
from which a guidance level can be derived for a short term
formaldehyde exposure. However, in order to have guidelines
available to direct a response in the case of a spill or ac-
cidental contamination, it has been decided to develop a short-
term guidance level for formaldehyde based upon the Yonkman
et al. (1941) study in humans.
The adverse effects resulting from daily consumption of
22 mg of formaldehyde in human subjects were mild pharyngeal
and gastric discomfort. The subjects initially had received
22 mg of formaldehyde per day for the first 14 days and there-
after the daily dosage of formaldehyde was increased every 7
or 14 days until it had reached 200 mg per day by the final
week (thirteenth). The dose of 22 mg of formaldehyde (the min-
imal effect level in humans) will be used in proposing guidance
level and a safety factor of 100 will be applied in the calcu-
lation since the observed adverse health effects are based on
only two human subjects.
In calculating the guidance level, children are assumed to
be exposure subjects, and gastrointestinal absorption of for-
maldehyde is assumed to be 100 percent in humans.
Accepting 0.314 mg/kg (22 mg/70 kg) as the minimal adverse
effect dose, calculation of a guidance level for a 10 kg child,
consuming 1 liter of water, are given below:
Calculations:
0.314 mg/kg x 10 kg = 0.031 mg/liter/day
1 liter/day x 100
The National Academy of Sciences (NAS, 1979) has suggested
that the chronic exposure level for formaldehyde in drinking
water be 0.11 mg/liter for an adult. This chronic exposure
level for formaldehyde (0.11 mg/liter) is based on the Yonkman
et al. (1941) study. It should be pointed out that considera-
tion of this study for deriving a short-term SNARL (1-day/b-
day) would have been more appropriate than for a chronic SNARL
value because (1) only two subjects had participated in the
above study and (2) results of recently completed studies
suggest that formaldehyde has carcinogenic potential in
laboratory animals.
Analysis
A sensitive fluorometric method for the measurement of
formaldehyde has been developed by Belman (1963). The fluoro-
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metric method is based on the fluorescence of 3,5-diacetyl-
1,4-dihydrolutidine formed from the reaction between acetyl-
acetone, ammonia, and formaldehyde (Nantzsch reaction). The
minimal detection level is 0.005 ug/mi. The fluorescence is
linear from 0.005 ug/ml to 1.0 ug/mi of formaldehyde. The
procedure is as follows:
1. Preparation of Reagent : 2M ammonium acetate and 0.02M
acetyl-acetone (2,4-pentanedione) at pH 6.0.
2. Reaction of Reagent with Formaldehyde : The reagent is
mixed with an equal volume of sample solution containing
formaldehyde and the mixture placed in a water bath for
60 minutes at 37 ) C. Remove samples and cool to room
temperature.
3. Fluorescence Measurement : The fluorescence is read after
cooling to room temperature. The maxima for fluorescence
excitation is 410 nm and for emission 510 nm.
Treatment
The literature concerning information on removal of for-
inaldehyde from ambient water is sparse (Giusti et al. 1974).
Conclusions and Recommendations
The guidance level for formaldehyde in drinking water is
proposed for short-term exposure. The potential for carcino-
genicity of this chemical has not been considered in developing
this guidance level. The short-term guidance level is 0.030
mg/liter for formaldehyde and is based on mild pharyngeal and
gastric discomfort in adult subjects.
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