-------
DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of "trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
-Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the Hfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as-^
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios.. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates.
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and cardno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxldty and carclno-
genldty) represent two of six scores developed (the remaining four reflect
IgnltabllUy, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined In U.S.
EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
Formic add 1s a colorless liquid at room temperature (Hawley, 1981).
It Is a strong reducing agent, and may react as both an add and an aldehyde
(Wagner, 1980). Formic acid Is produced as a coproduct during the manufac-
ture of acetic add from the liquid-phase oxidation of butane (CMR, 1984).
Celanese Corp In Pampa, TX, which has the capacity Jtp produce 25 million
- ' t "" . ,
pounds/year of the refined product. Is the only current domestic manufac-
turer of formic add. Union Carbide In Brownsville, TX, has a plant with a
capacity of 60 million pounds/year that Is presently Idle; the company
supplies this compound In the United States through Imports (CMR, 1984).
Common uses for formic acid have been Identified as textile dyeing and
finishing, Pharmaceuticals, rubber Intermediate, leather and tanning"
treatment,-catalysts, and others [Including oil well acidizing (CMR, 1984)].
In the atmosphere, formic add Is expected to be removed by reaction
with photochemlcally generated hydroxyl radicals and by wet deposition.
Based on experimental data, the half-life for reaction with hydroxyl
radicals was estimated to range between 29 and 50 days (Atkinson 1985). In
water, blodegradatlon screening studies Indicate that formic add would
blodegrade readily to CO- under aerobic conditions and to CO. and CH.
under anaerobic conditions (P1ne, 1958; Flna et al., 1960). Numerous bio-
degradation studies have been performed using standard BOO dilution water;
5-day BOO values ranging from 4.3-77.6% BOOT have been measured (Gaffney and
Ingols, 1961; Heukeleklan and Rand, 1955; Price et al., 1974; Takemoto et
al., 1981; Malaney and Gerhold, 1969; Placak and Ruchhoft, 1947). Chemical
hydrolysis, oxidation, volatilization and adsorption to suspended solids and
1v
-------
sediments are not expected to be significant fate processes In water. In
soil, formic acid Is expected to be mobile. B1odegradat1on under aerobic
and anaerobic conditions should be a significant fate process.
** -
Formic acid has been Identified In surface water, sediment, groundwater,
precipitation, ambient air, some fruits and beverages, and auto exhaust.
This compound has also been Identified 1n emissions from forest fires,
' **-..' ' : '
dlesel fuel combustion, lacquer manufacturers, plastics combustion, refuse
combustion', tobacco smoke and vegetation (Graedel, 1978; Graedel et al.,
1986). Formic add Is a major constituent of precipitation In both urban
and remote areas of the world, the combination of acetic and formic adds
can constitute as much as 59% (w/v) of free add present 1n remote areas
(Chapman et al., 1986). The mean concentration of formic add In unflltered
samples of precipitation collected from sites 1n Wisconsin, Virginia and
»
Illinois was 0.78, 0.64 and 0.21 mg/l, respectively (Chapman et al., 1986;
Keene and Galloway, 1984; Bachman and Peden, 1987). Unflltered rain samples
collected from remote areas of the South Indian Ocean, Venezuela and
Australia have been found to contain formic add at concentrations ranging
from undetectable to 0.98 mg/l (Mazurek and S1mone1t, 1986). At various
locations In California, the average and maximum concentrations of formic
acid 1n ambient air by year are as follows: 1976 - 2 and 7 ppb, respec-
tively; 1977 - 5 and 13 ppb, respectively; 1978 - 6 and 19 ppb, respec-
tively; and 1980 - 4 and 10 ppb, respectively (Altshuller, 1983). Formic
add has also been measured at several sites In the rural southwest United
States at concentrations ranging between a few tenths of a ppb and 3.5 ppb
(Altshuller, 1983). No data are available regarding the occurrence of
formic add In drinking water.
-------
Formic add occurs naturally In some fruits, vegetables, and leaves and
roots of plants (Wagner, 1980). The natural level of formic add 1n various
food and beverages such as fruit, fruit Juices, coffee, evaporated milk and
cheese has been found to be on the order ,of several mg/kg (U.S. FDA, 1976).
Dowden and Bennett (1965) reported a 24-hour TL of 175 mg/i for
""
blueglll sunflsh, Lepomls macrochlrus. exposed to formic add. The 24-hour
TLm for brine shrimp, Artemla sallna. exposed to formic add was 410
mg/l (Price et al., 1974). The 4-hour LC5Q of formic add to larvae of
the mosquito, Aedes aeqyptl. was 0.04X (v/v) (Kramer et al., 1983). Wlldlsh
et al. (1977) reported that herring, Clupea harengus. were neither attracted
nor repelled by exposure to a 1.25 mg/l solution of 88% formic acid. An
estimated BCF value of 0.23 for this compound suggests that formic acid will
not bloaccumulate significantly 1n aquatic organisms.
Bates .and Hurlbert (1970) reported a 0.08X survival rate after 30
minutes of exposure to a 0.012 M solution of formic add at a pH of 4.5 for
the flagellate, Euqlena qradlls var. baclllarls. Schafer et al. (1983)
estimated an oral LD5Q of >111 mg/kg for formic acid In the redwing black-
bird, Aqelalus phoenlceus. based on food consumption over an 18-hour period.
Absorption of formic add occurs by way of the gastrointestinal tract.
lungs, skin and urinary bladder (Schultz, 1883; Lund, 1948a). Rapid
gastrointestinal absorption of formic acid has been reported In humans
(Halorny, 1969a). Widespread distribution of formic add to the blood,
liver, kidney, brain, heart, spleen and testes 1n rabbits and mice has been
reported (LelsvouM et al., 1987; Sperling et al., 1953). Formic acid
undergoes oxidation to form CO- and water (von Oettlngen, 1959). The
reaction can occur In the liver, kidney, spleen, lungs. Intestinal mucosa.
gastrointestinal tract (by bacteria) and blood (Battelll, 1904; Flelg, 1907;
Popoff, 1875; Hoppe-Seyler, 1876). The primary site of sodium formate
v1
-------
oxidation 1s the liver (Malorny, 1969b). Rabbits and rats have been found '
to metabolize large amounts of formic add, whereas dogs appear to have a
dose-11m1t1ng ability to metabolize formic add (Lund, 1948a,b; Halorny,
1969b; Pohl, 1893). Excretion of formic add 1n the urine 1s highly
variable among species. In man, the half-life for formic acid excretion 1s
45-46 minutes (Malorny, 1969a).
: -...- « ' - -: :-' U;- ' "- " '"-'
No treatment-related effects were observed 1n men-Ingesting formic add
T- -»rv--V ;; H? >t ".', -. ... ' --''-; ->' ..;K- ..".- :iJ,«" . .
at 8 mg/kg/day for 4 weeks (Lebbln, 1916). Levels specified only as
"higher" caused local actions. Several subchronlc studies where formic add
was administered to rats In their diet or drinking water have been performed
\
(Sporn et al., 1962; Solmann, 1921; Flelg, 1907). Slight, but not signifi-
cant, growth Inhibition occurred at 0.5% 1n the diet (Sporn et al., 1962).
Decreased food Intake and growth Inhibition occurred at 360 mg/kg/day
(Solmann, 1921).
A series of multlgeneratlon studies of rats given calcium formate 1n
their drinking water have been reported by Malorny (1969b). Slightly
Increased phagocytosis In moderately Increased ret1culoendothel1al and
retlculohlstlocytic subcellular components 1n the lungs, spleen and abdom-
inal lymph nodes occurred In rats at 200 mg/kg/day (equivalent to 160
mg/kg/day formic add). There was no effect on reproduction. A NOEL of 160
mg/kg/day was Identified 1n these studies.
A variety of effects have been reported as a result of acute oral
exposure In man (Rosewarne. 1983; Jefferys and Wlsenman, 1980; Rajan et al.,
1985; Huhlendahl et al., 1978; Lambeth and Somasundaram, 1970; Mallzla et
al., 1977; Slgurdsson et al., 1983; Jacques, 1982). These effects Include
oral, pharyngeal, esophageal and gastrointestinal burns, mortality, Internal
hemorrhaglng, hematologlc and cardiovascular anomalies, renal failure, liver
damage, CNS depression, pylorlc obstruction and tracheal strictures.
-------
Mortality has occurred In humans at an oral exposure range of 429-643 nig/kg
formic acid (Jefferys and Wiseman, 1980).
In guinea pigs, Inhalation of 0.34-13.5 ppm formic add resulted In a
tt * -
dose-related occurrence of Impaired respiratory function (Amdur, 1960).
Acute oral and Inhalation data Indicate that mice, followed by rats, are the
most sensitive species to formic add poisoning.
*
No carcinogenic response occurred 1n a 3-generat1on drinking water study
In which Wlstar rats received 200 mg/kg/day calcium formate (Halorny,
1969b). Also, dermal exposure to 8% formic add 1n mice for up to 50 days
produced no evidence of carclnogenldty (Fre1 and Stephens, 1968).
Positive results occurred 1n three sex-linked lethality assays using D_.
melanoqaster and 1n one forward mutation assay 1n E_. coll (Stumm-Tegethoff,
1969; Demerec et al., 1951). A negative result occurred 1n a ONA Inactlva-
tlon assay 1n B_. subtnis (Freese et al., 1967).
Data were Insufficient to evaluate the carcinogenic potential of formic
add for humans; therefore, the compound was assigned to EPA group D, not
classifiable as to carclnogenldty to humans. Quantitative cancer
potencies, therefore, were not estimated. Data were Inadequate to derive
RfD values for either subchronlc or chronic Inhalation exposure to formic
add. An RfD of 2 mg/kg/day was derived for chronic oral exposure to formic
add from the NOEL of 200 mg/kg/day calcium formate (equivalent to 160
mg/kg/day formic add) 1n the multlgeneratlon reproduction study by Malorny
(1969b). The chronic RfD was adopted as the RfO for subchronlc oral
exposure to formic add. An RQ of 1000 pounds was derived for the chronic
toxldty of formic add based on reduced survival of offspring In rats In
the study by Sporn et al. (1962).
-------
TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER .."...... ." 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA . . . . 2
. 1.5. SUMMARY 3
\ -
2. ENVIRONMENTAL FATE AND TRANSPORT .1 . ...... 4
2.1. AIR ;'.". .;'-. . . 4
2.1.1. Reaction with Hydroxyl Radicals 4
2.1.2. Physical Removal Processes 4
2.2. WATER 4
2.2.1. Hydrolysis 4
2.2.2. Oxidation ........... 4
2.2.3. Photolysis 5
2.2.4. H1crob1al Degradation 5
2.2.5. Adsorption 6
- 2.2.6. Volatilization 6
2.3. SOIL 6
2.3.1. Chemical Degradation 6
2.3.2. Mlcroblal Degradation 6
2.3.3. Adsorption 6
2.4. SUMMARY 7
3. EXPOSURE 8
3.1. WATER 8
3.2. FOOD 8
3.3. AIR 9
3.4. DERMAL 10
3.5. SUMMARY 10
4. ENVIRONMENTAL TOXICOLOGY 12
4.1. AQUATIC TOXICOLOGY 12
4.1.1. Acute Toxic Effects on Fauna 12
4.1.2. Chronic Effects on Fauna 12
4.1.3. Effects on Flora 13
4.1.4. Effects on Bacteria and Other Microorganisms. . . 13
1x
-------
TABLE OF CONTENTS (cont.)
Page
4.2. TERRESTRIAL TOXICOLOGY 13
4.2.1. Effects on Fauna 13
4.2.2. Effects on Flora. - . ....... 14
4.3. FIELD STUDIES 14
4.4. AQUATIC RISK ASSESSMENT 14
4.5. SUMMARY i-V-t . .-. 14
5. PHARMACOKINETCS V . / . . V . . 17
.-, 5.1. ABSORPTION ;-...-. . ''?'.*'*'l'-"^-. 17
5.2. DISTRIBUTION 17
5.3. METABOLISM 19
5.4. EXCRETION 20
5.5. SUMMARY 23
6. EFFECTS . . . . '. . 24
6.1. SYSTEMIC TOXICITY. .;. .... 24
6.1.1. Inhalation Exposure 24
6.1.2. Oral Exposure 24
- 6.1.3. Other Relevant Information 26
6.2. CARCINOGENICITY 30
6.2.1. Inhalation 30
6.2.2. :ral. 30
6.2.3. 3ther Relevant Information. . 30
6.3. MUTAGENICITY 32
6.4. TERATOGENICITY 32
6.5. OTHER REPRODUCTIVE EFFECTS 32
6.6. SUMMARY 34
7. EXISTING GUIDELINES AND STANDARDS 36
7.1. HUMAN 36
7.2. AQUATIC 36
8. RISK ASSESSMENT 37
8.1. CARCINOGENICITY 37
8.1.1. Inhalation . 37
8.1.2. Oral 37
8.1.3. Other Routes 37
8.1.4. Weight of Evidence 37
8.1.5. Quantitative Risk Estimates 38
-------
TABLE OF CONTENTS (cont.)
Page
8.2. SYSTEMIC TOXICITY. . 38
8.2.1. Inhalation Exposure 38
8.2.2. Oral Exposure . . ." 38
9. REPORTABLE QUANTITIES , . 41
9.1. BASED ON SYSTEMIC TOXICITY 41
9.2. BASED ON CARCINOGENICITY ..._... 44
10. REFERENCES . . 46
APPENDIX A: LITERATURE SEARCHED 61
APPENDIX B: SUMMARY TABLE FOR FORMIC ACID 64
APPENDIX C: DATA USED TO GENERATE DOSE/DURATION - RESPONSE
GRAPHS FOR ORAL EXPOSURE TO FORMIC ACID 65
x1
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LIST OF TABLES
No. Title Page
5-1 Formic Add Concentrations In Tissue Compartments After
Five Dally Intravenous Doses 18
5-2 Urinary Excretion (Percent of Dose) of Formic Add 21
6-1 Effects of Acute Exposure to Formic Add In Humans 27
6-2 Oral LDsg Data for Formic Add. 29
6-3 LDso Values for Formic Add and Us Salts In the House. . . 31
6-4 Mutagenldty Data for Formic Acid ... '."'.' 33
9-1 Oral Toxldty Summary for Formic Add and Calcium Formate . . 42
9-2 Oral Composite Scores for Formic Add and Calcium Formate . . 43
9-3 Formic Acid: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 45
-------
LIST OF ABBREVIATIONS
AEL
BCF
BOD
BOOT
CAS
CNS
CS
DNA
PEL
GMAV
GMCV
GRAS
Koc
Kow
LC50
L°50
LOAEL
MED
NOAEL
PEL
pKa
ppb
ppm
ppt
RfD
RQ
RV
TLV
TWA
v/v
w/v
Adverse effect level
81oconcentrat1on factor
Biological oxygen demand
Biological oxygen"demand, theoretical
Chemical Abstract Service
Central nervous system
Composite score
Deoxyr1bonucle1c add
Frank effect level
Genus mean acute values
Genus mean chronic values
Generally recognized as safe
Soil sorptlon coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
Dose lethal to SOX of recipients
Lowest-observed-adverse-effect level
Minimum effective dose
No-observed-adverse-effect level
Permissible exposure level
Negative log 10 add dissociation constant
Parts per billion
Parts per million
Part per trillion
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Median tolerance level
Threshold limit value
Time-weighted average
Volume per volume
Weight per volume
X111
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Formic add 1s also known as amlnlc add, formyllc add, hydrogen
carboxyllc add and methanolc acid (SANSS, 1988). The structure, empirical
formula, molecular weight and CAS Registry number are as follows:
0
//
. HC
\
OH
Empirical formula: CH.O-
Molecular weight: 46.0
CAS Registry number: 64-18-6
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Formic add Is a colorless liquid with a.pungent odor (Hawley, 1981).
It Is a strong reducing agent, and may react as both an add and an
aldehyde, since the carboxyl group Is bound to a hydrogen atom rather than
an alkyl group (Wagner, 1980). Formic acid decomposes readily by dehydra-
tion, dehydrogenatlon or through a blmolecular redox reaction:
HCOOH -» H20 * CO (dehydration)
HCOOH -» H2 * C02 (dehydrogenatlon)
2 HCOOH -» H20 * C02 * HCHO (redox reaction)
Even at room temperature, the rate of formic add decomposition Is measur-
able; however, traces of water, Including the water formed by decomposition.
Inhibit the reaction (Wagner, 1980). Formic add 1s mlsdble with ethanol,
ethyl ether and glycerol (Wlndholz, 1983). Relevant physical and chemical
properties are as follows:
Melting point: 8.48C Wagner, 1980
Boiling point: 100.7°C Wagner, 1980
0136d -1- 03/14/89
-------
Vapor pressure (20°C): 34 mm Hg Boubllk et al., 1984
Water solubility: mlsdble Wlndholz, 1983
Log Kow: -0.54 Hansch and Leo, 1985
pKa (20°C): 3.75 Weast, 1985
Density (20°C): 1.220 g/cm3 Wagner, 1980
Flashpoint, open cup: 69°C Hawley, 1981
Odor threshold:
A1r: 49 ppm (v/v) Amoore .and Hautala, 1983
Water: 1700 ppm (w/v) Amoore and Hautala, 1983
1.3. PRODUCTION DATA '
Celanese Corp. In Pampa, IX, Is the only domestic manufacturer currently
producing formic add on a commercial scale (SRI, 1987). This plant has the
capacity to produce 25 million pounds/year of refined formic add (CMR,
1984). Union Carbide 1n Brownsville, TX, has a plant with a capacity of 6Q_
million pounds/year, which 1s currently Idle; the company markets the .
compound 1n the United States using a supply arrangement with overseas
producers (CMR, 1984). Formic acid 1s obtained as a coproduct during acetic
add production from the liquid-phase oxidation of butane (CMR, 1984).
Based on an estimated 2.5% growth rate between 1983 and 1988, the U.S.
demand for formic add during 1988 was projected to be 53 million pounds
/
(CMR. 1984).
1.4. USE DATA
Common uses for formic add have been Identified as textile dyeing and
finishing, Pharmaceuticals, rubber Intermediate, leather and tanning
treatment, catalysts, and others [Including oil well acidizing (CMR,
1984)]. Other applications Include use In the manufacture of formates,
oxalic add, organic esters, fumlgants, Insecticides, refrigerants, solvents
0136d -2- 04/12/89
-------
for perfumes and lacquers, and vinyl resin plastldzers, use In brewing
(antiseptic), silvering glass and ore flotation and use as a food additive
(U.S. FDA, 1988; Hawley, 1981).
** »
1.5. SUMMARY
Formic add 1s a colorless liquid at room temperature (Hawley, 1981).
It Is a strong reducing agent, and may react as both an add and an aldehyde
(Wagner, 1980). Formic acid Is produced as a coproduct during the manufac-
ture of acetic add from the liquid-phase oxidation of butane (CMR, 1984).
Celanese Corp In Pampa, TX, which has the capacity to produce 25 million
pounds/year of the refined product, 1s the only current domestic manufac-
V .
turer of formic add. Union Carbide 1n Brownsville, TX, has a plant with a
capacity of 60 million pounds/year, which Is currently Idle; the company.
supplies this compound 1n the United States through Imports (CMR. T984).
-^
Common used for formic add have been Identified as textile dyeing and
finishing, Pharmaceuticals, rubber Intermediate, leather and tanning
treatment, catalysts, and others [Including oil well acidizing (CMR, 1984)].
0136d -3- 04/12/89
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
2.1.1. Reaction with Hydroxyl Radicals. The rate constant for the
reaction of formic add vapor with photochemlcally generated hydroxyl
radicals 1n the atmosphere was experimentally determined to be 0.32xlO~la
to 0.545xlO'12 cm3 molecule'1 sec'1 at 25°C (Atkinson, 1985). Using
this range of values and assuming an average ambient hydroxyl radical
concentration of 5.0x10* molecules/cm3 (Atkinson, 1985), the hydroxyl
reaction half-life of formic add was estimated to range between 29 and 50
days.
2.1.2. Physical Removal Processes.. The complete water solubility of*
formic add and Us pKa value of 3.75 suggest that significant amounts of
this compound or Us anlons formed 1n the aerosol may be scavenged from thff
atmosphere by wet deposition. The amount of formic add occurring In the
atmosphere 1n partlculate form 1s expected to be negligible because of the
relatively high vapor pressure of this compound (34 mm Hg at 25°C) (Boubllk
et a!., 1984; E1senre1ch et a!., 1981). As a result, dry deposition of
formic add Is not expected to be a significant removal process In the
atmosphere.
2.2. WATER
2.2.1. Hydrolysis. Carboxyllc adds, such as formic add. are generally
resistant to chemical hydrolysis under environmental conditions (Harris,
1982).
2.2.2. Oxidation. The rate constant for reaction of formic add with
photochemlcally generated hydroxyl radicals In water was experimentally
determined to be 1.4xl08 M"1 sec'1 at pH 5, 2.45xlO» to S.lxlO9
M"1 sec"1 at pH 7 and 4.0xlO» M'1 sec"1 at pH 9 (Anbar and Neta,
1967; Dorfman and Adams, 1973). Assuming an average hydroxyl radical
0136d -4- 04/07/89
-------
concentration of IxlO"17 mol/i 1n natural sunlH water (Mill et al.,
1980), the respective oxidation half-lives of formic add at these pH levels
were estimated to be 16 years, 259-327 days and 201 days. These values
*« *
suggest that oxidation by reaction with photochemlcally generated hydroxyl
radicals 1n water would be too slow to be an environmentally significant
fate process. -.; -
2.2.3. Photolysis. The absorption spectra of formic acid Indicate that
1t will not absorb light 1n the environmentally significant range (wave-
length >290 nm) (Calvert and PUts, 1966). Therefore, photolysis of this
compound Is probably not a significant fate process.
2.2.4. M1crob1al Degradation. In the standard BOD dilution technique.
Incubation of 40 ppm formic acid for 3, 5, 10 and 20 days resulted 1n oxygen
consumption equivalent to 2.9, 14.4, 38.8 and 34.5% BOOT, respectively, when
ammonia was used as the nitrogen source of nutrient, and 2.1, 4.3, 38.8 and
38.8% BOOT, respectively, when nitrate was used as the nitrogen source
(Gaffney and Ingols, 1961). Heukeleklan and Rand (1955) reported that In
various blodegradatlon screening studies using standard BOD dilution water,
formic add had 5-day BOD values ranging between 5.8 and 77.6% BOOT. Other
experimenters have studied the blodegradatlon of formic add 1n standard BOO
dilution water with the following results: 50-100% BOOT In 1 day (Malaney
and Gerhold, 1969); 66% BOOT In 12 hours (McKlnney et al., 1956); 39.9% BOOT
1n 22-24 hours (Placak and Ruchhoft, 1947); 48-51% BOOT 1n 5 days and 60-68%
BOOT In 20 days (Price et al., 1974); 62% BOOT in 5 days and 95% BOOT In 20
days In synthetic seawater (Price et al., 1974); 40.5% BOOT In 5 days
(Takemoto et al., 1981); and 51.7% BOOT In 5 days In synthetic seawater
(Takemoto et al., 1981). Formic add 1s also susceptible to blodegradatlon
under anaerobic conditions (Brill et al., 1964; Speece, 1983; P1ne, 1958;
0136d -5- 03/14/89
-------
Flna et al., 1960). Formic acid 1s blodegraded to carbon dioxide under
aerobic conditions, and to carbon dioxide and methane under anaerobic condi-
tions (P1ne, 1958; Flna et al., I960). These data suggest that blodegrada-
*» *
tlon would be the dominant mechanism for the removal of formic add from
environmental waters. ; . , .... . ..'-'
2.2.5. Adsorption. Considering the complete water solubility of formic
acid and Us estimated K value of 12 (Section 2.3.3.), physical adsorp-
tion to suspended solids and sediments In water 1s not expected to be an
Important fate process.
2.2.6. Volatilization. The experimentally determined Henry's Law
constant for formic acid of ,1.67xlO"7 atm-mVmol at 25°C (Gaffney et
al., 1987} suggests that volatilization would not be a significant removal
mechanism from surface water (Thomas, 1982).
2.3. SOIL
2.3.1. Chemical Degradation. Formic acid 1s not expected to undergo
chemical hydrolysis under environmental conditions (Harris, 1982).
Pertinent data regarding other chemical degradation processes were not
located In the available literature dted 1n Appendix A.
2.3.2. H1crob1a1 Degradation. Based on the results of blodegradatlon
studies 1n aqueous systems, It appears that soil microorganisms would
readily blodegrade formic acid. Microbes capable of oxidizing formic acid
under aerobic and anaerobic conditions have been Isolated from soil (Kung
and Wagner, 1970; Pate! et al., 1978, 1979; Harada and Nagashlma, 1975;
Brown et al., 1964).
2.3.3. Adsorption. In most natural soils with pH >5.0, formic add will
be present In Its anlonlc form. The sorptlon of formate Ions on soils 1s
0136d -6- 03/14/89
-------
likely to depend on the Ion-exchange property, pH and particle size of the
soil. Because of their high water solubility, formate Ions may leach
readily from soils.
.:.:»' - -
2.4. SUMMARY
tt «
In the atmosphere, formic acid 1s expected to be removed by reaction
with photochemically generated hydroxyl radicals and by wet deposition.
Based on experimental data, the half-life for reaction with hydroxyl
radicals was estimated to range between 29 and 50 days (Atkinson, 1985). In
water, blodegradatlon screening studies Indicate that formic add would
blodegrade readily to C0_ under aerobic conditions and to CO. and CH
under anaerobic conditions (P1ne, 1958; F1na et al., 1960). Numerous bio-
degradation studies have been performed using standard BOO dilution water;
5-day BOD values ranging from 4.3-77.6% BOOT have been measured (Gaffney
Ingols, 1961; Heukeleklan and Rand, 1955; Price et al., 1974; Takemoto et
al., 1981; Malaney and Gerhold, 1969; Placak and Ruchhoft, 1947). Chemical
hydrolysis, oxidation, volatilization and adsorption to suspended solids and
sediments are not expected to be significant fate processes In water. In
soil, formic add Is expected to be mobile. Blodegradatlon under aerobic
and anaerobic conditions should be a significant fate process.
0136d -7- 04/07/89
-------
3. EXPOSURE
3.1. WATER
Levels of formic acid 1n water samples collected from various depths In
Lake Klzakl, Japan, ranged from undetectable to 30 ygC/l (Hama and
Handa, 1981). Formic acid was one of the most common organic acids found 1n
sediments of Lake Bowa, Japan. This compound was not found In the Inter-
~> f i ..." '4 -' w . ' - -
stltlal waters of the sediment, but was found In adsorbed form In and on the
sediment particles. The concentration of formic add In whole sediment
samples ranged between 0.5 and 9.5 ymol/g (23-437 yg/g) wet mud (Maeda
and Kawal, 1986). Groundwater near a wood-preserving facility In Pensacola,
PL, contained formic add at a concentration range of undetectable to 0.97
mg/l at various depths up to 18 m. Formic add may have been a product
rendered from the wood during treatment or a blodegradatlon product of the
solutes of creosote (GoerlUz et al., 1985).
3.2. FOOD
Formic add occurs naturally In some fruits, vegetables, and leaves and
roots of plants (Wagner. 1980). The natural formic add content found In
some foods and beverages Is as follows (U.S. FOA. 1976): fruits, 0.2-0.4
mg/kg; fruit Juices, 0.3-1.0 mg/kg; fruit syrups, 6.5-16.3 mg/kg; honey,
0.2-20 mg/kg; wines 0.01-3.4 mg/kg; coffee, roasted 13.5-20.0 mg/kg;
evaporated milk, 0.3-0.4 mg/kg; and cheese 0.2-3.0 mg/kg. Formic acid Is
used as a food additive and as a constituent of paper and paperboard used In
food packaging (U.S. FOA, 1988). Data from the early.1970s Indicate that
the average dally Intake (by age group) of formic add used as a food
additive Is as follows: 0-5 months, 0.01 mg; 6-11 months, 0.09 mg; 12-23
months, 0.18 mg; and 2-65 years, 0.43 mg (U.S. FDA, 1976).
0136d -8- 08/15/89
-------
3.3. AIR
The formation of formic add In the atmosphere 1s due primarily to
reaction of formaldehyde with free radicals (HO-, HO-») formed as a
result of photochemical reactions (Altshuller, 1983; Adewuyl et al., 1984).
Therefore, the concentration of formic add In the atmosphere generally will
be higher In urban areas than In rural areas and during summer than during
winter months. The concentration of formic acid In "Los Angeles, CA, air
samples collected between July and September 1984 ranged between 0.066 and
2.98 ppb (Kawamura et al., 1985). At various locations In California, the
average and maximum concentrations of formic acid In ambient air by year are
as follows: 1976 - 2 and 7 ppb, respectively; 1977 - 5 and 13 ppb, respec-
tively; 1978 - 6 and 19 ppb, respectively; and 1980 - 4 and 10 ppb, respec-
tively (Altshuller, 1983). Formic acid has also been measured at several
sites 1n the rural southwest United States. At a site northwest of Tucson,
AZ. concentrations of this compound ranging between 1.5 and 3.5 ppb were
reported during December., 1979 (Altshuller, 1983). At a site southeast of
Tucson, AZ, concentrations between a few tenths of a ppb and 3 ppb were
detected during July-August 1981 (Altshuller. 1983). A1r samples collected
at two remote sites In Arizona during January-February 1980 contained
-0.5-1.5 ppb (Altshuller, 1983). Atmospheric aerosol collected 0.4 and 3.5
km above a wet tropical forest In Guyana during June 1984 contained formic
acid at concentrations of <0.5 and 1 ng/m3 (0.27 and .0.53 ppt), respec-
tively (Gregory et al., 1986). Exhaust from a gasoline-powered automobile
was found to contain 9.3 ppb formic acid (Kawamura et al., 1985). Formic
acid was also Identified In emissions from forest fires, dlesel fuel combus-
tion, lacquer manufacturers, plastics combustion, refuse combustion, tobacco
smoke and vegetation (Graedel, 1978; Graedel et al., 1986).
0136d -9- 08/15/89
-------
Formic add has been Identified as one of the major constituents of
precipitation, particularly In remote areas of the world. The combination
of acetic and formic acids can constitute as much as 59% (v/w) of free acid
present In remote areas. The source of'thls chemical In these locations Is
probably anthropogenic (Chapman et al., 1986). , Unflltered rain samples
collected from remote areas of the South Indian Ocean, Venezuela and
Australia during 1980 and 1981 have been found to contain formic acid at
concentrations ranging from undetectable to 0.98 mg/i (Mazurek and
SlmoneH, 1986). The volume-weighted mean concentration of formic acid In
precipitation collected at two sites In Wisconsin between March 15 and
June 1, 1984, was 0.78 mg/8, In samples containing visible sediments and
0.44 mg/l 1n samples without sediments (Chapman et al., 1986). Keene and
Galloway (1984) found levels of formic acid ranging between 0.04 and 2.16
mg/i with a volume-weighted mean of 0.64 mg/i In 16 samples collected
between April 25 and October 1, 1983, at a site In central Virginia. The
mean concentration of formic and acetic acids 1n precipitation collected
during early spring months In central Illinois was 0.21 mg/a. (Bachman and
Peden, 1987). UnfUtered precipitation collected In Los Angeles, CA,
between November 1978 and April 1979 contained formic add at concentra-
tions of undetectable to 0.0055 mg/l (Mazurek and SlmoneH, 1986).
3.4. DERMAL
Data regarding human exposure to formic add by dermal contact were not
located In the available literature cited In Appendix A.
3.5. SUMMARY
Formic add has been Identified In surface water, sediment, groundwater,
precipitation, ambient air, some fruits and beverages, and auto exhaust.
0136d -10- 08/15/89
-------
This compound has also been Identified In emissions from forest fires,
dlesel fuel combustion, lacquer manufacturers, plastics combustion, refuse
combustion, tobacco smoke and vegetation (Graedel, 1978; Graedel et al..
** *
1986). Formic acid Is a major constituent of precipitation In both urban
and remote areas of the world. The combination of acetic and formic adds
can constitute as much as 59X (w/v) of free acid present In remote areas
(Chapman et al., 1986). The mean concentration of formic add In unflltered
samples of precipitation collected from sites 1n Wisconsin, Virginia and
Illinois was 0.78, 0.64 and 0.21 mg/l, respectively (Chapman et al., 1986;
Keene and Galloway. 1984; Bachman and Peden, 1987). Unflltered rain samples
collected from remote areas of the South Indian Ocean, Venezuela and
Australia have been found to contain formic add at concentrations ranging
from undetectable to 0.98 mg/l (Mazurek and Slmonelt, 1986). At various
locations In California, the average and maximum concentrations of formic
acid 1n ambient air by year are as follows: 1976 - 2 and 7 ppb, respec-
tively; 1977 - 5 and 13 ppb, respectively; 1978 - 6 and 19 ppb, respec-
tively; and 1980 - 4 and 10 ppb, respectively (Altshuller, 1983). Formic
acid has also been measured at several sites In the rural southwest United
States at concentrations ranging between a few tenths of a ppb and 3.5 ppb
(Altshuller, 1983). No data are available regarding the occurrence of
formic add In drinking water.
Formic acid occurs naturally In some fruits, vegetables, and leaves and
roots of plants (Wagner, 1980). The natural level of formic add In various
food and beverages such as fruit, fruit juices, coffee, evaporated milk and
cheese has been found to be on the order of several mg/kg (U.S. FDA, 1976).
0136d -11- 08/15/89
-------
4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Dowden and Bennett (1965) assessed
the acute toxldty of formic add to blueglll sunflsh, Lepomls macrochlrus.
Tests were conducted In reconstituted water of unspecified quality at an
unspecified test temperature. The Investigators reported a 24-hour TL of
175 mg/i. . _
Price et al. (1974) assessed the acute toxIcHy of formic add to brine
shrimp, Artemla sallna. Brine shrimp were exposed to formic add 1n 150
ml wide-mouth bottles at 24.5°C for 24 hours. The Investigators reported
a 24-hour TLm of 410 mg/l. ._,. .
Kramer et al. (1983) assessed the acute toxldty of formic add to
larvae of the mosquito, Aedes aegyptl. Second-third Instar larvae were
exposed to formic acid In glass beakers or small jars. Larvae (10-20) were
exposed to 50 ml of test solution for 4 hours at 22-24°C. The Investi-
gators reported an average 4-hour LC,. of 0.04X (v/v) from the results of
three trials In which the results of the separate experiments differed by
less than £lOX.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY -- Pertinent data regarding the effects of chronic
exposure of aquatic fauna to formic acid were not located In the available
literature cited In Appendix A.
4.1.2.2. BIOACCUHULATION/BIOCONCENTRATION No measured steady-state
BCF value for formic add was found In the literature. Based on the
regression equation, log BCF = 0.76 log K - 0.23 (Lyman et al., 1982)
and a log KQW value of -0.54 (see Section 1.2.), a BCF value of 0.23 Is
estimated for this compound. This value suggests that formic add will not
bloaccumulate significantly In aquatic organisms.
0136d -12- 03/14/89
-------
4.1.2.3. OTHER EFFECTS WUdlsh et al. (1977) assessed the prefer-
ence/avoidance response of herring, Clupea harenqus. to formic add 1n sea
water, and reported that herring were neither attracted nor repelled by
exposure to a 1.25 mg/l solution of 88% formic add.
- . . , ..j . , j
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY Pertinent data regarding the toxic effects of
exposure of aquatic flora to formic add were not located 1n the available
^.'-.-.. ':.- -~- .': . -V.' '
literature dted In Appendix A.
4.1.3.2. BIOCONCENTRATION Pertinent data regarding the bloconcen-
tratlon potential of formic add In aquatic flora were not located In the
available literature cited In Appendix A.
4.1.4. Effects on Bacteria and Other Microorganisms. Bates and Hurlbert
(1970) assessed the effect of formic acid on the viability of populations of
the flagellate, Euqlena gradlls var. baclllarls. Tests were conducted at
27°C 1n 100 ml of media 1n 250 ma, Ehrlenmeyer flasks. All cultures were
Inoculated with cells to give an Initial concentration of 2xl03
cells/ml. Changes 1n cell mass were determined colorImetMcally using a
540 y (green) filter. The Investigators reported a 0.08% survival rate
after 30 minutes of exposure to a 0.012 M solution of formic add at a pH
of 4.5.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Schafer et al. (1983) determined the acute oral
toxlclty .of formic acid to the redwing blackbird, Agelalus phoenlceus.
Birds were trapped In the wild and preconditioned to captivity for 2-6 weeks
before the start of testing. The Investigators estimated an oral LD5Q of
>111 mg/kg for formic add based on food consumption over an 18-hour period.
0136d -13- 03/14/89
-------
4.2.2. Effects on Flora. Pertinent data regarding the effects of ,
exposure of terrestrial flora to formic add were not located In the
available literature cited 1n Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of formic add on flora and fauna
1n the field were not located In the available literature cited In
Appendix A. '
4.4. AQUATIC RISK ASSESSMENT
Insufficient data regarding the effects of exposure of aquatic fauna and
flora to formic add prevented the development of a freshwater criterion by
the method of U.S. EPA/OWRS (1986) (Figure 4-1). Development of a criterion
for formic add In freshwater will require conducting acute assays with a
salmonld, a fish (other than blueglll sunflsh) or an amphibian, benthlc an3~~
planktonlc crustaceans, an Insect, a representative from a non-Chordate/
Arthropod phylum, and an Insectan family or phylum not represented previ-
ously. Development of a criterion will also require conducting at least two
chronic assays with fauna, one assay with an alga or vascular plant and at
least one bloconcentratlon study.
No data were located regarding the effects of exposure of marine fauna
and flora to formic add, preventing the development of a saltwater
criterion by the method of U.S. EPA/OWRS (1986).
4.5. SUMMARY
Dowden and Bennett (1965) reported a 24-hour TL of 175 mg/l for
blueglll sunflsh, Lepomls macrochlrus. exposed to formic add. The 24-hour
TL for brine shrimp, Artemla sallna. exposed to formic add was 410
mg/l (Price et al., 1974). The 4-hour LC5Q of formic acid to larvae of
the mosquito, Aedes aegyptl. was 0.04X (v/v) (Kramer et al., 1983). Wlldlsh
et al. (1977) reported that herring, Clupea harenqus. were neither attracted
0136d -14- 04/07/89
-------
Fami ly
*i
Chordate (Salmon id-fish)
tti
Chordate (warmwater fish)
*i
Uhordate (fish or amphibian)
*<* '
Crustacean (planktonic)
*b
Crust acear. (bentnic)
fct.
Inceet an
t!V
non-fcr t h r o pod / -Ch or d ate
*£;
New Insect an or phylum
represent at ive
'#9
al gae
*iO
Vascular plant
TEST TYPli
Acute*
Nft
175-
NA
NP
Nft
Nft
Nft
Nft
Nft
Nft
Chronic*
Nft
Nft
, Nfl
Nft
Nft
Nft
Nft
Nft
Nft
Nft
BCF*
Nft
Nft
Nft
Nft
Nft
Nft
Nft
Nft
Nft
Nft
'S4-hou" TL-
for bluegill .unfi.h Leoorni
FIGURE 4-1
Organization Chart for Listing GHAVs, GMCVs and BCFs Required to Derive
Numerical Water Quality Criteria by the Method of U.S. EPA/OWRS (1986) for
the Protection of Freshwater Aquatic Life from Exposure to Formic Acid
0136d .
-15-
04/07/89
-------
nor repelled by exposure to a 1.25 mg/i solution of 88X formic add. An
estimated BCF value of 0.23 for this compound suggests that formic acid will
not bloaccumulate significantly 1n aquatic organisms.
Bates and Hurlbert (1970) reported a 0.08% survival rate after 30
minutes of exposure to a 0.012 M solution of formic add at a pH of 4.5 for
the flagellate, Euqlena qradlls var. badllarls. . Schafer et al. (1983)
estimated an oral ID... of >111 mg/kg for formic add In the redwing black-
bird, Age!a1 us phoenlceus. based on food consumption over an 18-hour period.
0136d -16- 04/07/89
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
Absorption of formic add by way of the gastrointestinal tract, lungs,
skin and urinary bladder has been repprted 1n several mammalian species
(Schultz, 1883; Lund, 1948a). In addition, rapid absorption of formic add
.- :/- -:"- " J-; ' ' ' : ' ' ' ; '" .-''. ' .£?',
from the gastrointestinal tract has been reported to occur In humans. '".;"-%'
.".A*.'* *
Malorny (1969a) measured plasma levels of formic add of 11.8 mg/100 ml at '".'">
10 minutes'after administration of a 4.44 g dose of sodium formate to a vli^t
human, von Oettlngen (1959) speculated that some formic add may undergo
m1crob1al degradation before absorption can occur.
5.2. DISTRIBUTION . . ;-
. Single dally doses of 100 mg/kg formic add, buffered to pH 7.4, were ,.;
-administered Intravenously to 15 male New Zealand rabbits on 4 consecutlve'-
days, followed by Intravenous administration. of 100 mg/kg l4C-form1c add
on the 5th day (L1es1vuor1 et al., 1987). Formic add and 14C-formate
were distributed by the blood to the brain, heart, liver, kidney and urine
(Table 5-1). Peak concentrations In all compartments occurred within the
first hour, except that peak concentrations In the brain occurred at 2
hours, suggesting that the blood-brain barrier slowed passage to this organ.
Highest tissue levels of radlolabel were located In the liver and kidney,
highly perfused organs of metabolism and excretion. Concentrations In the
urine were higher than 1n any of the tissues.
Sperling et al. (1953) reported that when 14C-labeled sodium formate
was given by Intraperltoneal Injection to large Osborne-Hendel rats, the
majority of the dose not excreted In the urine (-20%) was concentrated In
the fat and/or protein fractions of the testes, lungs, spleen, heart, liver,
stomach and kidneys. In this study, the highest concentrations of
14C-formate were found 1n the protein of the stomach and liver.
0136d -17- 04/07/89
-------
TABLE 5'-l
Formic Acid Concentrations 1n Tissue Compartments After Five Dally
. : ...Intravenous Doses* : ... -:
a !ij i .-..:.,
Tissue
Compartment
Blood
T Brain
Heart
Liver
Kidney
Urine
~
Time After the
Fifth Dose
(hours)
1
2
,20
. -r -1 '->- :
2
20
' 1
2
20
1
2
20
1
2
20
1
2
20
Total
(vmol/g)
0.7*0.4
0.5>0.2
0.2*0.1;
--1.1*0.4
1.3*0.6
. 0.7*0.4
0.8*0.3
0.7*0.3
0.5*0.2
1.5*0.5
1.1*0.4
0.3*0.05
1.7*0.7
1.0T0.6
0.4*0.1
44*22
32*~12
0.6*0.2
. - ... .
14C-Labeled
(wmol/g)
0.3*0.1
0.2*0.1
0.1*0.05
0.4*0.2 "-''
0.6T0.3
O.U0.05
0.6*0.3
0.4*0.2
O.H0.05
0.9*0.5
0.7*0.4
0.2*.0.05
0.8*0.5
0.7*0.2
0.2*.0.05
27*12
25*8
0.1*0.01
t ..
Difference
0.4*0.1
0.2T0.1
; 0.2*.0.05
;:" 0.4*0. 2 -
0.5*0.2
0.4*0.1
0.6*0.2
0.3*0.1
0.3*0.1
0.4*0.2
0.5*0.2
O.U0.05
0.6*0.4
0.8*0.4
0.2*0.05
17f8
9*"6
o.sTo.i
*Source: L1es1vuor1 et al., 1987
0136d
-18-
04/07/89
-------
5.3. METABOLISM
Formic add 1s an endogenous compound Important 1n Intermediary metabo-
lism (U.S. EPA, 1985). Upon absorption, formic add Is Immediately trans-
formed Into formate (Malorny, 1969a). ..Although some formate 1s excreted
unaltered, It Is also oxidized to form carbon dioxide and water (von
Oettlngen, 19S9). Retained formate Is Incorporated Into proteins, I1p1ds
and nucleic adds (Tracor-JUco, 1974). Oxidation of formate has been
demonstrated \n_ vitro 1n liver, kidney, lung, spleen, Intestinal mucosa and
In blood extracts (BatteTM, 1904; Flelg, 1907). Formic add has also been
shown to be decomposed by bacteria 1n the gastrointestinal tract (Popoff,
1875; Hoppe-Seyler, 1876). At least 1n rat liver and Jejunum, formate
oxidation Involves a catalase-hydrogen peroxide complex and enzymes such as
xahthlne oxldase, uHcase, monoamlne oxldase and D-amlno add oxldase (Orcr~
and Rappoport, 1959). A study using rabbits Indicates that the liver
appears to be the primary site of formate oxidation (Malorny. 1969b). The
half-lives of formate (presumably administered Intravenously) In rabbits
with excised livers vs. Intact rabbits were 130 and 25 minutes,
respectively. Rabbits were found to oxidize large doses of formic add
(Lund, 1948b; Bastrup, 1947). Dogs can oxidize completely only small doses
of formic add (0.143 g/kg), and larger doses are excreted partially
unchanged (Pohl, 1893; Grehant and Qulnquaud, 1887). Also, man can
completely metabolize only limited doses of formic add; unaltered formic
add Is excreted In the urine (Autenrleth, 1919; Welngarten, 1932). Malorny
(1969b) reported biological half-lives of formic add following Intravenous
Injection as follows: dog, 77 minutes; cat, 67 minutes; rabbit, 32 minutes;
guinea pigs, 22 minutes; rats, 12 minutes. Malorny (1969b) generalized that
the more rapid oxidation of formic acid by herbivores compared with
0136d -19- 04/07/89
-------
carnivores may reflect a greater supply of follc add 1n herbivores. Follc
acid antagonists such as methotrexate Inhibited formic add oxidation.
L1es1vuor1 et al. (1987) stated that the rat 1s a poor model for formic acid
toxldty 1n humans because rats metabolize formic add through the follc
*« * -
acid cycle more efficiently than humans. They suggest that rabbits and dogs
behave more closely to humans 1n this regard. . ,'; ,
When administered orally, the amount of Ingesta present In the gastro-
intestinal tract and the concentration of the test material, as well as the
magnitude of the dose, play a role In determining the rate of oxidation of
formic add (von Oettlngen, 1959).
5.4. EXCRETION
,, Several studies that measured urinary excretion of" formic add In
rabbits, rats, dogs and man are summarized In Table 5-2. The extent
urlnary excretion of formic acid Is highly variable both within and between
species, but appears to be generally dose-dependent 1n oral studies.
Urinary excretion was -4 times higher In rats given a dose of 185 mg/day
compared with rats given 19 mg sodium formate (Malorny, 1969b). Sperling et
al. (1953), however, found little variation In urinary excretion 1n large
male Osborne-Hendel rats given Intraperltoneal Injections of ~2 or 5 mg/kg
/
radlolabeled formate. Over an 8-day collection period, these rats excreted
-82% of the Injected dose of radioactivity as expired 14C02 and -1.4% 1n
the feces. The total radioactivity excreted averaged 88% of the dose; -78%
of the dose was excreted within the first 24 hours. The Investigators
estimated a half-life of ~7 days for radioactivity not excreted within the
first 24 hours.
0136d -20- 04/07/89
-------
TABLF. 5-2
Urinary Excretion (Percent of Dose) of Formic Acid
0
o.
Species/Strain Compound Route
Oog/NR NR oral
NR oral
NR oral
sodium Intravenous
formate
7* sodium subcutaneous
formate
Rabbi t/NR NR oral
sodium subcutaneous
formate
Rat calcium oral
formate
sodium oral
formate
Rat/Osborne- Na-14C- Intraper Honeal
o Hendcl formate
>
-v
Dose Percent
of Dose
20 g 26
5 g 65
1 g 8-9
4 g 55
198 mg/kg 42
1 g/kg 14.2-19.3
303-317 mg/kg 2-8
185.4 ing/day 13.8 I
-19 mg/day 3
NR 5.3
Reference
Schotten, 1883
Grehant and
Qulnquaud. 1887
Epplnger, 1913
Grehant and
Qulnquaud, 1887
Lund, 1948a
Epplnger, 1913
Lund, ]948b
Nalorny, 1969b
Malorny, 1969b
Sperling et al.,
1953
o - '
d
^
oo
-------
TABLE 5-2 (cont.)
CJ
cr
OL.
Species/Strain
Human
Compound Route
sodium oral
formate
sodium Intravenous
formate
Dose Percent
of Dose
20 g 18
4 g 25-50
' Reference
Autenrleth, 1919
Uelngarten, 1932
NR = Not reported
to
I
to
us
-------
5.5. SUMMARY
Absorption of formic add occurs by way of the gastrointestinal tract.
lungs, skin and urinary bladder (Schultz, 1883; Lund, 1948a). Rapid gastro-
intestinal absorption of formic add has been reported In humans (Malorny,
1969a). Widespread distribution of formic add to the blood, liver, kidney,
brain, heart, spleen and testes 1n rabbits and mice has been reported
(LelsvouM et al., 1987; Sperling et al., 1953). Formic add undergoes
oxidation :to form, CO. and water (von Oettlngen, 1959).. The reaction can
.occur In the liver, kidney, spleen, lungs. Intestinal mucosa, gastrointes-
tinal tract (by bacteria) and blood (Battelll, 1904; Flelg, 1907; Popoff,
1875; Hoppe-SeyTer, 1876). The primary site of sodium formate oxidation Is
the liver (Malorny, 1969b). Rabbits and rats have been found to metabolize
.large amounts of formic add, whereas dogs appear to have a dose-Umltlng^-
abllUy to metabolize formic acid (Lund, 1948a,b; Malorny, 1969b; Pohl,
1893). Excretion of formic add In the urine Is highly variable among
species. In man, the half-life for formic add excretion Is 45-46 minutes
(Malorny, 1969a).
0136d -23- 04/07/89
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Completed studies regarding the subchronlc
and chronic toxlclty of formic add as a result of Inhalation exposure were
*» »
not located; however, a subchronlc Inhalatton study of formic acid In rats
and mice Is being conducted (NTP, 1988). ' '
6.1.2. Oral Exposure. : ' ,".
:-. 6.1.2.1. SUBCHRONIC No treatment-related effects occurred In an
unspecified number of men given -8 mg/kg/day of formic add dally 1n
lemonade for 4 weeks (Lebbln, 1916). At doses specified as "higher" than
the Initial dose, however, "local actions" (presumably the effects of an
acid Irritation) were observed. The duration of exposure at the higher dose
was not specified. - "
Groups of eight rats (sex and strain were not specified) were given
casein-based diets containing 0.5 or 1.0% formic acid for 5-6 weeks to
determine effects on growth and protein efficiency (Sporn et al., 1962).
Control rats received basal diet without added formic add. Slight growth
Inhibition was reported In both treated groups, but the extent was not
statistically significant.
Solmann (1921) administered formic acid In drinking water to groups of
3-6 rats at concentrations of 0.01, 0.01 and 0.1% for 11, 14 and 15 weeks,
respectively. Additional groups were given 0.25X for 15 weeks (after 12
weeks at 0.01%) and 0.5% for 9 weeks (after 17 weeks at 0.1%). The use of
controls was not reported. Variables measured Included food and water
consumption and growth rate. Dosages estimated by the Investigators were
0136d -24- 04/07/89
-------
8.1-10.25 mg/kg/day at 0.01X, 90.0 mg/kg/day at 0.1X, 160.0 mg/kg/day at
0.25X and 360 rag/kg/day at 0.5X. No effects were reported at 0.01-0.25X.
At 0.5X, both food consumption and growth rate were depressed.
Sporn et al. (1962) administered formic acid 1n drinking water at 0 or
IX to 10 male and 50 female white rats grouped as follows: group I -
untreated controls; group II - females on formic add throughout the experi-
ment; group III - males on formic add throughout the.experiment; group IV -
males and females on formic add throughout the experiment; group V -
females on formic acid during lactation. Endpolnts evaluated were
restricted to reproductive performance, hematologyi-^ver nitrogen content
and adrenal ascorbic add content. Evaluations were conducted after 1, 3
and 7 months of exposure. The most significant observation was a marked
reduction In survival of offspring on postpartum day 7 1n groups II, III and
IV; however, survival data were not analyzed statistically (Section 6.5.).
Hyperchromic anemia, basophlllc neutropenla, slight lymphocytosls and
leuckocytosls were also observed 1n rats exposed to formic add.
6.1.2.2. CHRONIC The chronic oral toxldty of formic acid was
Investigated over five generations (3 years) In Wlstar rats (Malorny,
1969b). The first generation consisted of 8 male and 24 female test rats
and 8 control rats. The test rats received 0.2X (150-200 mg/kg/day, as
determined by the author) calcium formate In their drinking water throughout
the study. No treatment-related effects on reproduction, growth or organ
function (not specified) were reported. Hlstopathologlc examination
revealed slightly Increased phagocytosis In moderately Increased retlculo-
endothellal and retlculohlstlocytlc elements In the lungs, spleen and
abdominal lymph nodes; however, no tox1colog1cally significant effects could
be attributed to chronic administration of calcium formate.
0136d -25- 08/15/89
-------
This study was repeated with a drinking water concentration of 0.4% ,
(300-400 rag/kg/day, as estimated by the author) calcium formate for two
generations over 2 years (Malorny, 1969b). Hlstopathologlc examination of
unspecified tissues revealed no treatment-related effects.
6.1.3. Other Relevant Information. Solmann (1921) reported that no
effects occurred In men given 150 mg/kg/day for "some time.* Stern (1906)
reported that vertigo, nausea, vomiting, albumlnurla, tenesmus, dyspnea and
hypothermia occurred In men taking 2000-3000 mg formic acid several times/
day. The duration of exposure was not specified. Data regarding acute oral
exposures of humans to mixtures containing formic add (for example,
descaling compounds) are summarized In Table 6-1. Oral, pharyngeal,
esophageal and gastrointestinal alteration and perforation are commonly
reported effects of oral exposure to formic add. Additional effects'"
Include mortality, Internal hemorrhaglng, hemolysls, hematologlc and
cardiovascular effects, altered blood chemistry, metabolic addosls, renal
failure, liver toxldty, CNS depression, pyloMc obstruction and tracheal
strictures. One of six people died after Ingesting 30-45 g (429-643 mg/kg)
of formic add; this level has been Identified as the threshold for
mortality (Jefferys and Wiseman, 1980). Further, 14/16 humans died after
Ingesting 45-200 g (643-2847 mg/kg) of formic add, and Jefferys and Wiseman
(1980) concluded that consumption of 60 g (851 mg/kg) resulted 1n death In
all cases.
Dose-related Impaired respiratory function occurred 1n guinea pigs
during 1-hour Inhalation exposures to 0.34-13.5 ppm formic add (Amdur,
1960). In addition, the Irritant effects of formic acid were found to be
more potent than those of formaldehyde.
Oral LDcQ values for formic add In dogs, rats, mice and rabbits are
presented 1n Table 6-2. Mice, followed by rats, appear to be the most
0136d -26- 04/07/89
-------
o
CO
0.
TABLE 6-1
Effects of Acute Exposure to Formic Acid In Humans
Route
Age/Number/Sex
Exposure
Response
Reference
Oral 52 years/1/F
NR/16/NR
o
-J
\
CO
NR/23/NR
NR/6/NR
16-46 years
(mean, 25 years)/
30 M. 23 F
2 years/1/M
unknown amount of
SOX formic acid
solution
45-200 g formic
acid
5-30 g formic
acid
30-45 g formic
acid
NR
50 100 ml of a
solution con-
taining >50X
formic acid
(decalclfter)
Severe gastrointestinal and oral
Irritation. CNS depression,
Internal hemorrhaylng
Mortality due to gastrointestinal
hemorrhage In 14/16, acute renal
failure, Intravascular coagula-
tion, pneumonltls
Oropharyngeal burns, gastro-
intestinal ulceratlon and per-
foration
One mortality, severe gastro-
intestinal homonhaying, intra
vascular coagulation, renal
Failure, liver toxlclty
15/53 mortalities, severe gastro-
intestinal Irritation, facial/
oral burns, gastrointestinal
hemorrhaglng, pneumonltls,
cardiovascular effects, acute
renal failure; lethal effect at
>10 mi oral
Death
Rosewarne, 1983
Jefferys and
Wiseman. 1980
Jefferys and
Ulseman, 1980
Jefferys and
Wiseman, 1980
Rajan et al., 1985
NGhlcndahl ct al.,
1978
-------
CJ
o»
Q.
TABLE 6-1 (cont.)
Route
Age/Number/Sex
Exposure
Response
Reference
Oral
chtldren/19/NR
I
ro
00
i
21 years/1/M
56 years/1/H
60 years/1/H
Oral/ 35 years/1/H
dermal
Dermal 15/1/F
unknown amount of
decalclfters con-
taining formic
acid
1 cup formic acid
55* formic acid.
1.6% phosphoric
acid, 4X qulnollne
unknown quantity
of formic acid
sprayed In face
with Jet of formic
acid
NR
Esophageal and oral burns.
gastrointestinal hemorrhaglng
Oral esophageal and gastric
burns, gastrointestinal hemor
rhaglng, pylorlc obstruction
Renal failure, heart failure.
death
Oropharyngeal burns, gastro-
intestinal Irritation
Gastrointestinal Irritation,
burns on face and thorax
Systemic effects Included meta-
bolic acldosls, hemolysts.
gastrointestinal Irritation,
hemogloblnurla, leukocytosls,
elevated blood urea; depressed.
potassium and sodium levels.
HQhlendahl et al.,
1978
Lambeth and
Somasundaram, 1970
Jacques, 1982
Hallzla et al.,
1977 s
Hallzla et al..
1977
Stgurdsson et al.,
1983
NR = Not reported
-------
TABLE 6-2
Oral 1050 Data for Formic Add
Species
Dog
Rat
Mouse
Rabbit
L050
(mg/kg)
4000
1210
1830
1100
700
1100
>4000
Reference
Sax, 1984
Sax, 1984
Guest et al..
NIOSH, 1988
NIOSH, 1988
Malorny, 1969b
Guest et al.,
1982
1982
0136d
-29-
04/07/89
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sensitive species, and rabbits and dogs appear to be the least sensitive
species to orally administered formic acid. For mice, LD5Q values of 142
and 940 mg/kg were reported for Intravenous and IntraperKoneal administra-
tion, respectively (Guest et al., 1982). LD5Q values for several salts of
formic add In mice are presented 1n Table 6-3. Sodium formate Is clearly
the least toxic salt by either oral or Intravenous administration. Varia-
tions In toxlclty probably reflect the toxlclty of the Individual cations.
Inhalation LC.Q data were available only for rats'and mice. The !5-m1nute
LC5Q values were 15,000 and 6200 mg/m3 for rats and mice, respectively
(NIOSH, 1988); mice are more than 2 times as sensitive than rats to formic
add vapor. ......
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenlclty
formlc add by Inhalation exposure were not located 1n the available
literature cited In Appendix A.
6.2.2. Oral. In a 3-generat1on study, gross and hlstopathologlc examina-
tions were performed on 250 Mlstar rats that were given a dosage of 200
mg/kg/day calcium formate In their drinking water for 2 years (Malorny,
1969b). Examination of the digestive tract, liver, kidneys and "other
tissues" revealed no evidence of cardnogenlclty; however, whether this was
a comprehensive examination of all organs and tissues 1s unclear from this
translation.
6.2.3. Other Relevant Information. The epidermal carcinogenic potential
of formic add was Investigated In a study where the ears of groups of 10
Inbred male Swiss mice were painted with 0 or 8% formic acid In distilled
water, twice/week for 2, 5, 10, 20 or 50 days (Fre1 and Stephens, 1968).
0136d -30- 04/07/89
-------
TABLE 6-3
1050 Values for Formic Add and Its Salts 1 ft-the House*
Substance
L050
(mg/kg)
1050 Range
{ mg/kg)
Calculated According
to Formate Ion
Equivalents
Per os_
Formic add
Sodium formate
Potassium formate
Ammonium formate
Calcium formate
1100
11.200
5500
2250
1920
1000-1200
9600-12,800
5000-6000
2050-2460
1280-2560
1076
7410
2950
1606
1330
Intravenous
Formic add
Sodium formate
Potassium formate
Ammonium formate
Calcium formate
145
807
95
410
154
138-151
800-813
93-97
408-412
150-158
142
534
51
293
107
*Source: Malorny, 1969b
0136d
-31-
04/07/89
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There was no effect on the Incidence of hyperplasla, epidermal thickness,
the presence of Inflammatory exudate or the hlstologlcal appearance of the
tissues.
6.3. MUTA6ENICITY
»* -.
Limited mutagen1c1ty data were available for formic acid (Table 6-4).
Positive results occurred In three sex-linked lethality assays using Droso-
phlla melanogaster and In one forward mutation assay In Escherlchla coll
(Stumm-Tegethoff, 1969; Demerec et al., 1951). Negative results were
obtained In a ONA 1nact1vat1on assay 1n ONA donor strain Bacillus subtllls
60009 (Freese et al., 1967). Stumm-Tegethoff (1969) speculated that formic
acid Inhibited catalase, allowing the accumulation of peroxides and free
radicals that Interfere with correct DNA replication.
6.4. TERATOGENICITY - . -
Malorny (1969b) reported that sodium formate Injected Into the air cell
of chicken eggs at 48-96 hours of Incubation at 5, 10 or 20 mg/egg had no
effect on embryo survival or body weight, and was "teratogenlcally unremark-
able." Data were not located regarding the developmental toxldty of formic
add In mammals.
6.5. OTHER REPRODUCTIVE EFFECTS
In the drinking water study by Sporn et al. (1962) (see Section
6.1.2.1.). formic add administered to rats at IX 1n the water resulted 1n a
marked decrease In neonatal survival at 7 days compared with untreated
controls. In this experiment, female rats were exposed for 7 months,
presumably Including the prematlng period through lactation. Decreased
neonatal survival was not observed 1n the offspring of rats treated only
during lactation. Survival data were not analyzed statistically.
0136d -32- 04/07/89
-------
o
_J
co
Q.
Assay Indicator/Organise
DMA Bacillus subtil Is
Inactlvatlon 60009
Reverse Escherlchta coll
utatlon B/Sd-y/1. 3. 4. S;
B/Sd 4/3. 4
' Sex-linked Drosophjla
co lethality *elanoqaster
i
0. elanogaster
D. elanoqaster
TABLE 6-4
Hutagenlclty Data for Foralc Acid*
Application Concentration Activating Response Cement
or Dose Systea ,
liquid 10~> to 10~> H MR - NC
suspension . ;
plate 0. 0050-0. OQ70X MR » NC
Incorporation . " .
vapor exposure 0.1X NA » NC
larval feeding 0.1X NA » NC
larval feeding 0.1X NA » foralc acid
stabilized at
pH 7.5 lowered
: Mitatton rate
Reference
freese et al..
1967
Oenerec et al..
1951
Stuan-Tegethoff.
1969
Stum-Tegethoff.
1969
Stuon-Tegethoff.
1969
*Purlty of the compound was not reported.
NR . Not reported; NA . not applicable
oo
wD
-------
Malorny (1969b) provided rats with drinking water containing 0.2%
calcium formate that provided a dosage of calcium formate estimated by the
Investigator at 150-200 mg/kg/day for five generations (see Section
6.1.2.2.). There was no effect on reproduction as determined by the number
**
of offspring/litter or the body weight or length of the offspring. Without
providing substantiating data, the Investigator reported that there was no
effect on reproduction with calcium formate at 0.4% 1n studies that had
progressed through two generations.
6.6. SUMMARY
No treatment-related effects were observed 1n men Ingesting formic add
at 8 mg/kg/day for 4 weeks (Lebbln. 1916). Levels specified only as
"higher" caused local actions. Several subchronlc studies where formic add
was administered to rats In their diet or drinking water have been performed
(Sporn et al., 1962; Solmann, 1921; Flelg, 1907). Slight, but not signifi-
cant, growth inhibition occurred at 0.5% In the diet (Sporn et al., 1962).
Decreased food Intake and growth Inhibition occurred at 360 mg/kg/day
(Solmann, 1921).
A series of mult1generat1on studies of rats given calcium formate 1n
their drinking water have been reported by Malorny (1969b). Slightly
Increased phagocytosis In moderately Increased retlculoendotheHal and
retlculohlstlocytic subcellular components 1n the lungs, spleen and
abdominal lymph nodes occurred In rats at 200 mg/kg/day. There was no
effect on reproduction. A NOEL of 200 mg/kg/day was Identified In these
studies. Sporn et al. (1962) observed a decreased survlvabUHy In
offspring during the first 7 days of life born to a first generation of rats
exposed to 1.0% formic add 1n drinking water.
0136d -34- 07/03/90
-------
A variety of effects have been reported as a result of acute oral
exposure 1n man (Rosewarne, 1983; Jefferys and Wlsenman, 1980; Rajan et
* *
al., 1985; MQhlendahl et al., 1978; Lambeth and Somasundaram, 1970; Mallzla
et al., 1977; Slgurdsson et al., 1983; Jacques, 1982). These effects
Include oral, pharyngeal, esophageal and gastrointestinal burns, mortality.
Internal hemorrhaglng, hematologlc and cardiovascular anomalies, renal
failure, liver damage, CNS depression, pylorlc obstruction and tracheal
strictures. Mortality has occurred In humans at an oral exposure range of
429-643 mg/kg formic add (Jefferys and Wiseman, 1980).
In guinea pigs, Inhalation of 0.34-13.5 ppm formic acid resulted In a
' ' . ' j '-',','
dose-related occurrence of Impaired respiratory function (Amdur, 1960).
Acute oral and Inhalation data Indicate that mice, followed by rats, are the-
most sensitive species to formic acid poisoning.
No carcinogenic response occurred In a 3-generatlon drinking water study
In which Wlstar rats received 200 mg/kg/day of calcium formate (Malorny,
1969b). Also, dermal exposure to 8% formic acid 1n mice for up to 50 days
produced no evidence of cardnogenlclty (Fre1 and Stephens, 1968).
Positive results occurred In three sex-linked lethality assays using 0.
melanogaster and In one foward mutation assay In E.. coll (Stumm-Tegethoff,
1969; Oemerec et al., 1951). A negative result occurred In a DNA Inactlva-
tlon assay In B_. sub tills (Freese et al., 1967).
0136d -35- 08/15/89
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The OSHA (1985) PEL for occupational exposure . to formic add Is 9
mg/m3. ACGIH (1988) adopted an 8-hour TWA-TLV of 5 ppm (-9 mg/m3) and
recommended that an STEL of 10 ppm (-18 mg/m3) be adopted. The TWA-TLV Is
designed to protect humans from Irritating effects on the eyes, respiratory
tract and possibly on the skin. The RQ for formic acid based on aquatic
toxlclty Is currently 5000 (U.S. EPA, 1988).
The U.S. EPA (1985) has verified an oral RfD of 2 mg/kg/day for formic
add based on chronic and subchronk toxlclty 1n rats (see Section
8.2.2.2.). After a comprehensive safety review, the U.S. FDA (1980)
affirmed the GRAS status of formic add as an Ingredient 1n human food.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to formic acid were not located In the available literature dted
In Appendix A.
0136d -36- 08/15/89
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8. RISK ASSESSMENT
Statements concerning available literature 1n this document refer to
published, quotable sources and are-In no way - meant to Imply that
confidential business Information (CBI), which this document could not
address, are not In existence. From examination of the bibliographies of
the CBI data, however, It was determined that CBI data that would alter the
approach to risk assessment or the risk assessment values presented herein
do not exist.
8.1. CARCINOGENICITY
8.1.1. Inhalation. Studies of the Inhalation carclnogenldty of formic
acid or Its formates were not located In the available literature; however,
the NTP Is conducting a subchronlc Inhalation study of formic acid In rats
and mice (NTP, 1988).
8.1.2. Oral. Malorny (1969b) exposed Wlstar rats to 200 mg/kg/day formic
acid In their drinking water for three generations. No evidence of carclno-
genldty was reported, although this study cannot be considered an adequate
study of the carclnogenldty of formic add.
8.1.3. Other Routes. Frel and Stephens (1968) reported that mice exposed
dermally (ear) to 8X formic add, twice/week for 2, 5, 10, 20 or 50 days
showed no evidence of a carcinogenic response.
8.1.4. Weight of Evidence. The negative carclnogenldty results from the
drinking water study reported by Malorny (1969b) provide Insufficient
evidence to assess the carcinogenic potential of formic add or calcium
formate In rats. In addition, the negative carclnogenldty results reported
by Fre1 and Stephens (1968) are also Inadequate for the evaluation of the
carcinogenic potential of formic add. Data were not located regarding the
carcinogenic potency of formic add In humans. Therefore, using the U.S.
0136d -37- 04/07/89
-------
EPA (1986a) cancer assessment guidelines, formic add 1s classified as an
EPA Group D carcinogen - not classifiable as to carcinogenic potential In
humans.
8.1.5. Quantitative Risk Estimates. The lack of positive data precludes
estimation of carcinogenic potencies for formic acid or Its formates for
either Inhalation or oral exposure.
^.- ' . '*' " *" '-' '
8.2. SYSTEMIC TOXICITY
.-:.-..». :-:.--: .:';: ' -., ' . ---' ' '' " " *: ' *; ''b~'-VV 3
8.211. Inhalation Exposure. Pertinent data regarding the subchronlc or
chronic Inhalation exposure to formic add or Us formates were not located
In the available literature cited In Appendix A.
8.2.2. Oral Exposure.
, :\ *
..." . » -
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) Formic add Is
an endogenous substance Involved In Intermediary metabolism (U.S. EPA~
1985). which has been granted GRAS status by the U.S. FDA (1980).
Therefore, U 1s reasonable to expect that the toxic potency of formic acid
should be low.
The available toxldty data are confusing. In humans, the critical
effect associated with acute 1ngest1on appears to be oropharyngeal add
/'
burns and gastrointestinal Irritation, which were reported at a dose range
of 5-30 g (Jefferys and Wiseman, 1960). A dose range of 34-45 g was
considered the threshold for mortality. Solmann (1921), however, reported
that there were no adverse effects In men given 150 mg/kg/day (10.5 g/day
for 70 kg man) for "some time." Lebbln (1916) reported no effects In men
given 8 mg/kg/day (0.56 g/day) for 4 weeks; unspecified higher doses
resulted In "local actions." The human data are Insufficient to estimate a
reliable NOAEL that may serve as the basis for an RfD.
0136d -38- 04/07/89
-------
Three subchronlc oral studies using rats with formic add were
considered. Sporn et al. (1962) reported a slight and not statistically
*. *
significant reduction 1n growth rate 1n rats fed diets containing 0.5 or
1.0% formic acid. Assuming a food factor for rats of 0.05 (U.S. EPA,
1986b), these dietary concentrations are equivalent to dosages of 250 and
500 mg/kg/day, respectively. In a drinking water study, formic add at 1%
for 7 months was associated with neonatal mortality and hematologlc changes
1n the adult rats (Sporn et al., 1962). Assuming rats weigh 0.35 kg and
Ingest 0.049 i of drinking water/day (U.S. EPA, 1986b). an equivalent
dosage of 1400 mg/kg/day can be estimated. In another drinking water study, -
Solmann (1921) reported reduced food consumption and growth rate 1n rats at
0.5% formic add. The Investigators estimated the dosage at 360 mg/kg/day^
«.
No effects were observed at 0.25%.
The animal studies discussed above were largely limited to evaluating
effects on rates of food and water Intake and growth. In addition, the
study by Sporn et al. (1962) evaluated reproductive performance and limited
hematologlc endpolnts. No study, however, Included hlstopathologlc examina-
tions. Therefore, these studies are Insufficient for derivation of an oral
RfO for subchronlc exposure, and the chronic RfD of 1.6 mg/kg/day (rounded
to 2 mg/kg/day) based on the Halorny (1969b) study (Section 8.2.2.2.), Is
adopted as being protective for subchronlc oral exposure as well.
8.2.2.2. CHRONIC EXPOSURE -- Chronic oral data are restricted to the
mult1generat1on study 1n rats In which caldum formate was administered In
drinking water. A slight Increase 1n phagocytosis 1n lungs, spleen and
abdominal lymph nodes (but no effects on reproduction) were observed 1n rats
maintained for over five generations on drinking water containing 0.2%
calcium formate (Malorny, 1969b). The Investigators estimated the dosage of
calcium formate at 150-200 mg/kg/day. In a later study with 0.4% caldum
0136d -39- 07/03/90
-------
formate (300-400 mg/kg/day). which was still 1n progress, no hlstopathologU
lesions were reported after 2 years (two generations). These data support
the selection of 200 mg/kg/day for calcium formate as a chronic NOEL In
rats. U.S. EPA (1985) applied an uncertainty factor of 100 (10 for extrapo-
i - :
latlon from animals to humans and 10 to protect unusually sensitive 1nd1-
:. " "
vlduals) to derive a verified oral RfD for formic add of 2 mg/kg/day. This
derivation Implies that calcium formate dissociates to formate 1n biological
systems, and the RfD for formic acid Is derived by analogy to formate. In
the derivation of this RfD, correction has been made for the ratio of the
molecular weight of formic acid to calcium formate, and 200 mg/kg/day should
be considered a NOEL for calcium formate. The equivalent dosage of formic
acid would be 160 mg/kg/day. The NOEL for formic add of 160 mg/kg/day,
equivalent to 9.9 g/day for a 70 kg human, 1s above the lower dosage of 5 g
associated with oropharyngeal burns and gastrointestinal Irritation In
humans acutely exposed to the add Uself (Jefferys and Wiseman, 1980).
Because the Irritation reported by Jefferys and Wiseman (1980) can be
attributed to acute exposure to the add at levels not expected to be
encountered 1n the environment, the rat NOEL of 160 mg/kg/day can serve as
the basis for an RfD. Furthermore, Solmann (1921) reported no adverse
effects In humans exposed to formic add at 150 mg/kg/day for "some time."
Application of an uncertainty factor of 100 results 1n an RfD for formic
add of 1.6 mg/kg/day, which would be rounded to 2 mg/kg/day. Confidence In
the key study Is medium because of Us long length and because
hlstopathologU examination was performed. Confidence In the data base Is
low, therefore confidence 1n the RfD 1s also low.
0136d -40- 07/03/90
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxIcUy of formic acid to humans and animals 1s discussed In
Chapter 6. Subchronlc and chronic oral studies 1n laboratory animals with
formic add and calcium formate reported sufficiently for evaluation and
consideration are summarized 1n Table 9-1. In Chapter 8, a chronic RfD for
formic acid was calculated given the assumption that at physiologic pH
calcium formate exists primarily as the formate anlon. In Table 9-1, the
dosage of formic add or calcium formate 1s expressed In terms of formic
acid equivalents In mg/kg/day, and the equivalent human dose Is expressed as
mg formic acld/kg/day.
Effects In rats associated with prolonged exposure to formic acid
4MB
Include depressed growth rate (Sporn et a!., 1962; Solmann, 1921), reduced
survival of offspring (Sporn et a!., 1962) and slightly decreased phagocyto-
sis In lung, spleen and lymph nodes (Halorny, 1969b). The Inhibition of
growth reported 1n rats fed diets containing formic add (Sporn et al.,
1962), however, was not statistically significant, and the Inhibition In
growth In rats fed formic add In the drinking water (Solmann, 1921) was
accompanied by decreased food Intake and 1s not considered a toxlcologlc
effect of the chemical. Therefore, CSs are not calculated for growth Inhi-
bition In these studies. Although the quality of the Sporn et al. (1962)
and Malorny (1969b) reports Is marginal at best, CSs for reduced survival of
offspring and for Increased phagocytosis are calculated 1n Table 9-2.
The RV for both effects Is 1, Indicating that both effects were
associated with high dosages, and the CSs derived therefore reflect only the
severity of the effect observed. Therefore, the higher CS 1s calculated for
reduced neonatal survival reported by Sporn et al. (1962). Although the
0136d -41- 04/07/89
-------
CO
o»
ex
TABLE 9-1
Oral Toxtctty Sunnary for Formic
Average
Species/ Weight*
Strain (kg)
Rat/NR 0.35
Rat/NR 0.35
£ Rat/NR 0.35
i
Rat/Wlstar 0.35
Compound/
Vehicle
formic acid/
diet
formic acid/
water
formic acid/
water
calcium
formate/water
Exposure
O.SX of diet for
5-6 weeks
O.SX In drinking
for 9 weeks
IX In drinking
water for up to
7 months
0.2X In drinking
water for five
generations
Transformed
Animal Dose
Expressed as
Formic Add
(mg/kg/day)
250
360
1400
160
Acid and Calcium Formate
Equivalent
Human Dose
Expressed as
Formic Ac1d>>
(mg/kg/day)
43
62
239
27
tt'.
Response
' t-
Slight growth Inhibition .
Decreased appetite and growth
Inhibition
Reduced survival of offspring
Increased phagocytosis.
Increased retlculoendothellal
and rettculohlstlocytlc cells..
Reference
Sporn et
1962
Solmann,
Sporn et
1962
>
Nalorny.
»!..
1921
1..
1969b
'Reference value from U.S. EPA (1980) used.
Calculated by multiplying the animal dose expressed as mg/kg/day formate by the cube root of the ratio of the animal body weight to the
reference body weight for man of 70 kg.
cThe weight of calcium formate Is converted to the weight of formic add by multiplying the weight of calcium formate by the ratio of the
molecular weight of formic acid divided by the molecular weight of calcium formate and dividing by 2: (2 x 46.02/130.12) 0.707
NR - Not reported .
o
to
-------
TABLE 9-2
Oral Composite Scores for Formic Add and Calcium Formate
Compound
Formic
add
Calcium
formate
Spedes/
Strain
rat/NR
rat/
Wlstar
Animal Dose
Expressed as
Formic Add
(mg/kg/day)
1400
160
Chronic
Human MED
Expressed as
Formic Add*
(mg/kg/day)
16,730
1.915
RVd Effect RVe CS
1 Reduced survival 8 8
of offspring
1 Slightly Increased 2 2
phagocytosis
RQ Reference
1000 Sporn
et al.,
5000 Halorny,
1969b
i
1962
'Equivalent human dose as mg/kg/day In Table 9-1 multiplied by 70 kg to express the HEO In ing/day for a 70
kg human.
NR = Not reported
-------
survival data cannot be analyzed statistically, the data do suggest that .w.
neonatal survival was reduced. Therefore, the CS of 8, equivalent to an RQ
of 1000, Is selected for the chronic toxldty of formic add (Table 9-3).
9.2. BASED ON CARCINOGENICITY
Carclnogenldty data, summarized In Section 6.2., consist of an Inade-
quate negative study using Wlstar rats exposed to 200 mg/kg/day of calcium
formate 1n their drinking water for five generations (Malorny, 1969b).
Since formic add was classified as EPA Group 0 - not classifiable as to
human cardnogen1c1ty, an F factor could not be derived and formic add 1s
not placed In a Potency Group. Hazard ranking for formic add, therefore,
cannot be based on cardnogenldty.
0136d -44- 04/07/89 '
-------
TABLE 9-3
Formic Acid
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
i. " s ' ' ' :' *
Species/sex: rats/M, F
Duration: <7 months
MED*: 16,730 mg/day
Effect: reduced neonatal survival
Reference: Sporn et al., 1962
RVd: 1
RVe: 8
Composite Score: 8
RQ: 1000
'Equivalent human dose
0136d -45- 04/07/89
-------
10. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1988.
*« -
Threshold Limit values and Biological Exposure Indices for 1988-1989.
Cincinnati, OH. p. 22, 39.
Adewuyl, Y.G., A.S. Cho, R.P. Tsay and G.R. Carmlchael. 1984. Importance
of formaldehyde In cloud chemistry. Atmos. Environ. 18: 2413-2420.
Altshuller, A.P. 1983. Measurements of the products of atmospheric photo-
chemical reactions In laboratory studies and 1n ambient air - Relationships
between ozone and other products. Atmos. Environ. 17: 2383-2427.
Amdur, M.O. 1960. The response of guinea pigs to Inhalation of formalde-
hyde and formic add alone and with a sodium chloride aerosol. Int. J. A1r
Pollut. 3(4): 201-220.
Amoore, J.E. and E. Hautala. 1983. Odor as an aid to chemical safety: Odor
threshold compared with threshold limit values and volatilities for 214
Industrial chemicals 1n air and water dilution. J. Appl. Toxlcol. 3:
272-290.
Anbar, M. and P. Neta. 1967. A compilation of specific blmolecular rate
constant for the reactions of hydrated electrons, hydrogen atoms and
hydroxyl radical with Inorganic and organic compounds In aqueous solution.
Int. J. Appl. Rad. Isotopes. 18: 493-523.
0136d -46- 04/07/89
-------
Atkinson. R. 1985. Kinetics and mechanisms of the gas-phase reactions of
the hydroxyl radical with organic compounds under atmospheric conditions.
Chem. Rev. 85: 69-201.
Autenrelth. W. 1919. No title provided. Munch. Med. Wchnschr. 66: 862.
(Cited In von Oettlngen, 1959}
Bachman, S.R. and M.E. Peden. 1987. Determination of organic acid anlons
1n precipitation by 1on chromatography exclusion. Water Air Soil Pollut.
33: 191-198.
Bastrup, J.T. 1947. On the excretion of formic add In experimental
*
poisoning with methyl alcohol. Acta. Pharmacol. Toxlcol. 3: 312. (Cited
1n von Oettlngen, 1959)
Bates, R.C. and R.E. Hurlbert. 1970. Effect of acetate on Euqlena gradlls
var. baclllarls as a function of environmental conditions. J. Protozool.
17(1}": 134-138.
BattelH, F. 1904. Oxydatlon de 1'aclde formlque par les extralts des
tlssus anlmaux en presence de peroxyde d'hydroqene. Compt. Rend. Acad. Scl.
(Cited In von Oettlngen, 1959}
Boubllk, T., V. Fried and E. Hala. 1984. The Vapor Pressures of Pure
Substances: Selected Values of the Temperature Dependence of the Vapour
Pressures of Some Pure Substances 1n the Normal and Low Pressure Region.
Vol. 17. Elsevler Scl. Publ., Amsterdam, Netherlands, p. 45.
0136d -47- 04/07/89
-------
Brill, W.J., E.A. Wolln and R.S. Wolfe. 1964. Anaerobic formate oxidation:
A ferredoxln-dependent reaction. Science. 144: 297-298.
Brown, L.R., R.J. Strawlnsk! and C.S. McCleskey. 1964. The Isolation and
characterization of Methanomonas methanooxldans. Can. J. Mlcroblol. 10:
791-799.
Calvert, J.G. and J.N. PHts, Jr. 1966. Photochemistry. John Wiley and
Sons, Inc., New York. p. 428-430.
Chapman, E.G., D.S. Sklarew and J.S. FUcklnger. 1986. Organic adds 1n
springtime Wisconsin precipitation samples. Atmos. Environ. 20: 1717-1725.
CMR (Chemical Marketing Reporter). 1984. Chemical Profile: Formic Add.
Schnell Publishing Co., New York. December 31, 1984.
Crockett, P.W., B. K1l1an, K.S. Crump and R.B. Howe. 1985. Descriptive
methods for using data from dissimilar experiments to locate a no-adverse-
tox1c-effects region In the dose-duration plane. Prepared by K.S. Crump and
Company, Inc., under Contract No. 68-01-6807 for the Environmental Criteria
and Assessment Office, U.S. EPA, Cincinnati, OH.
Demerec, M., G. Bertanl and J. Flint. 1951. Survey of chemicals for
mutagenlc action on E_. coll. Am. Natural. 85(821): 119-136.
Dorfman, L.M. and G.E. Adams. 1973. Reactivity of the hydroxyl radical In
aqueous solution. National Bureau of Standards, Washington, DC.
NSRD-NBS-46. NTIS COH-73-50623. p. 17-20, 24-31.
0136d -48- 04/07/89
-------
Dowden, B.F. and H.F. Bennett. . 1965. Toxldty of selected chemicals to
certain animals. J. Mater Pollut. Control Fed. 37(9): 1308-1316.
*» *
Durkln, P. and W. Meylan. 1988. User's Guide for D2PLOT: A program for
dose/duration graphs. Prepared by Chemical Hazard Assessment Division.
Syracuse Research Corporation under Contract No. 68-C8-0004 for Environ-
mental Criteria and Assessment Office, U.S. EPA, Cincinnati, OH.
Elsenrelch, S.J., B.B. Looney and J.D. Thornton. 1981. Airborne organic
contaminants of the Great Lakes ecosystem. Environ. Scl. Techno!. 15(1):
30-38.
Epplnger, H. 1913. No title provided. W1en. Klin. Rundschau. 27: 49.
(Cited 1n von Oettlngeni 1959)
Flna, L.R., H.J. Slncher and D.F. Oecou. 1960. Evidence for the production
of methane from formic acid by direct reduction. Arch. Blochem. Blophys.
91: 159-162.
Flelg, C. 1907. Etude physlologlque de quelques composes formlques. Int.
Pharmaco. 17: 147. (Cited In von Oettlngen, 1959)
Freese, E.B., J. Gerson, H. Taber, H.J. Rhaese and E. Freese. 1967.
Inactivating DNA alterations Induced by peroxides and peroxide-containing
agents. Hutat. Res. 4: 517-531.
0136d -49- 04/07/89
-------
Frel, J.V. and P. Stephens. 1968. The correlation of promotion of tumor
growth and Induction of hyperplagla In epidermal two-stage cardnogenesU.
Br. J. Cancer. 22: 88-92. (Cited 1n Tracor-JHco, 1974)
Gaffney, P.E. and R.S. Ingols. 1961. Nitrate as the nitrogen source In BOD
dilution water. Water Sewage Works. 108: 91-95.
Gaffney, J.S., G.E. StreH, W.D. Spall and J.H. Hall. 1987. Beyond add
rain. Environ. Scl. Techno!. 21(6): 519-524.
- 4
GoerlHz, O.F., D.E. Troutman, E.M. Godsy and B.J. Franks. 1985. Migration
of wood preserving chemicals 1n contaminated groundwater 1n a sand aquifer
at Pensacola, Florida. Environ. Sc1. Techno!. 19: 955-961.
Graedel, T.E. 1978. Chemical Compounds In the Atmosphere. Academic Press,
New York. p. 211.
Graedel, T.E., D.T. Hawkins and L.D. Claxton. 1986. Atmospheric Chemical
/
Compounds. Sources, Occurrence and Bloassays. Academic Press, New York.
p. 345.
Gregory, G.L., R.C. Harrlss, R.W. Talbot, et al. 1986. A1r chemistry over
the tropical forest of Guyana. J. Geophys. Res. 91: 8603-8612.
Grehant, N. and Qulnquaud. 1887. Que devlennent lesformlates IntroduUs
dans 1'organlsme? Compt. Rend. Acad. Sc1. 104: 437. (Cited 1n von
Oettlngen, 1959)
0136d -50- 04/07/89
-------
Guest, 0., G.V. Katz and B.O. AstHl. 1982. Saturated monocarboxyllc
adds. In.: Patty's Industrial Hygiene and Toxicology, Vol. 2C, 3rd ed.,
G.D. Clayton and F.E. Clayton, Ed. Jotin Wiley and'Sons, Inc., New York.
p. 4902-4987.
Hama, T. and N. Handa. 1981. Volatile organic acids.. In lake water; their
gas chromatographlc determination and ecological significance. Rlkuslugaku
Zasshl. 42: 8-19.
Hansch, C. and A.J. Leo. 1985. Medchem Project. Issue No. 26. Pomona
College, Claremont, CA.
-^i
Harada, T. and Y. Nagashlma. 1975. Utilization of alkylether compounds by
soil bacteria. J. Ferment. Techno!. 53: 218-222.
Harris, J.C. 1982. Rate of hydrolysis. In.: Handbook of Chemical Property
Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed. McGraw
H111 Book Co., New York. p. 7-1 to 7-48.
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 476.
Heukeleklan, H. and M.C. Rand. 1955. Biochemical oxygen demand of pure
organic compounds. J. Water Pollut. Control Assoc. 29: 1040-1053.
Hoppe-Seyler, F. 1876. Ueber die Processe der Gahrungen und Ihre Bezlehung
zum Leben der Orgalnlsmen. Pfluger's Arch. ges. Physlol. 7: 1. (Cited In
von Oettlngen, 1959)
0136d -51- 04/07/89
-------
Jacques, S. 1982. Acute renal failure following 1ngest1on of formic add.
Nurs. Times. 78(31): 1312-1315.
*» * '.
Jefferys, D.B. and H.M. Wiseman. 1980. Formic add poisoning. Postgrad,
Hed. J. 46(661): 761-762.
Kawamura, K., L. Ng and I.R. Kaplan. 1985. Determination of organic adds
::- f -.:- --'ov-' ? . »vf , -fin-" ^ ' *< ' "- "'^ "''* '-''*
(C1-C10) 1n the atmosphere, motor exhausts and engine oils. Environ. Scl.
Techno!. 19: 1082-1086.
Keene, W.C. and J.N. Galloway. 1984. Organic acidity In precipitation of
North America. Atmos. Environ. 18: 2491-2497.
Kramer, V.C., D.J. Schnell and K.W. Nlckerson. 1983. Relative toxldty of
organic solvents to Aedes aegvptl larvae. 3. Invertebr. Pathol. 42(2):
285-287.
Kung, H. and C. Wagner. 1970. Oxidation of C, compounds by Pseudomonas
Sp. MS. Blochem. J. 116: 357-365.
Lambeth, J. and K. Somasundaram. 1970. Pylorlc obstruction due to formic
add Ingestlon. Hed. J. Malaysia. 24(3): 187-189.
Lebbln. 1916. No title provided. Blochem Centralbl. p. v1, 83. (Cited
1n Solmann, 1921)
0136d -52- 04/07/89
-------
UeslvuoM, J., V.M. Kosma, Q. Naukkarlnen and H. Savolalnen. 1987.
Kinetics and toxic effects of repeated Intravenous dosage of formic add 1n
rabbits. Br. J. Exp. Pathol. 68: 853-861.
Lund, A. 1948a. Metabolism of methanol and formic add In dogs. Acta
Pharmacol. Toxlcol. 4: 108. (Cited 1n Tracor-JUco, 1974)
Lund, A. 1948b. Metabolism of methanol and formic add 1n rabbits. Acta.
Pharmacol. Toxlcol. 4: 99-107. (Cited 1n Tracor-JHco, 1974)
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill Book Co., New York. p. 5-5. ^
Maeda, H. and A. Kawal. 1986. Determination of organic adds In the lake
sediment. Nippon Sulsan Gakka1sh1. 52: 1205-1208.
Malaney, G.W. and R.M. Gerhold. 1969. Structural determinants In the
oxidation of aliphatic compounds by activated sludge. JJK Ind. Waste Conf.,
Purdue Univ. Ext. Serv. 112: 249-257.
Mallzla, E., C. Reale, P. P1etropaol1 and G.C. De RH1s. 1977. Formic acid
Intoxication. Acta Pharmacol. Toxlcol. 41(2): 342-347.
Malorny, G. 1969a. Metabolism studies with sodium formate and formic add
1n man. Z. Ernaehrungswlss. 9(4): 340-348. (In German with English trans-
lation) (Cited In Tracor-JUco, 1974)
0136d -53- 04/07/89
-------
Malorny, G. 19695. Acute and chronic toxldty of formic add and Us
formlates. Z. Ernahrungswlss. 9(4): 332-339. {In German with English
translation)
> »
Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a
hazardous undertaking. Cancer Res. 35: 1379-1386.
Hazurek, M.A. and B.R.T. Slmonelt. 1986. Organic components In bulk and
wet-only precipitation. CRC Cr1t. Rev. Environ. Contam. 16: 73.
McKlnney, R.E., H.D. Tomllnson and R.L. Wllcox. 1956. Metabolism of
aromatic compounds by activated sludge. Sewage Ind. Wastes. 28: 547-557.
Mill, T., D.G. Hendry and H. Richardson. 1980. Free-radical oxldants In
natural waters. Science. 207: 886-887.
Muhlendahl, D.E., U. Oberdlsse and E.G. Krlenke. 1978. Local Injuries by
accidental Ingestlon of corrosive substances by children. Arch. Toxlcol.
39: 299-314.
NIOSH (National Institute for Occupational Safety and Health). 1988. RTECS
(Registry of Toxic Effects of Chemical Substances). Online. CAS No.
64-18-6.
NTP (National Toxicology Program). 1988. Chemical Status Report. 10/06/88.
0136d -54- 04/07/89
-------
Oro, J. and O.A. Rappoport. 1959. Formate metabolism In animal tissues.
II. The mechanism of formate oxidation. J. B1o1. Chem. 234(7): 1661-1665.
(Cited In Tracor-JUco, 1974)
OSHA (Occupational Safety and Health Administration). 1985. Occupational
Standards. Permissible Exposure Limits. 29 CMR 1910.10.00. p. 655-659.
Patel, R.N., C.T. Hou and A. Felix. 1978. Mlcroblal oxidation of methane
and methanol: Isolation of methane-utilizing bacteria and characterization
of a facultative methane-utilizing Isolate. J. Bacterlol. 136: 352-358.
Patel, R.M., S.L. Hoare and D.S. Hoare. 1979. Acetate-l-14C assimilation
-~mv
by Obligate methylotrophs. Pseudomonas. Hethanlca and Hethyloslnus trlcho-
sporlum. Antonle Van Leeuwenhoek. 45: 499-511.
P1ne, M.J. 1958. Methane fermentation of formate by Methanobacnius
omel1ansk11. J. Bacterlol. 75: 356-359.
Placak, O.R. and C.C. Ruchhoft. 1947. Studies of sewage purification.
XVII. The utilization of organic substrates by activated sludge. Sewage
Works J. 19: 423-440.
Pohl, J. 1893. No title provided. Exper. Path. U. Pharmakol. 31: 281.
(CHed In von Oettlngen, 1959)
Popoff, L. 1875. Uber die sumpfgahrung. Arch Ges. Physlol. 10: 113.
(Cited In von Oettlngen, 1959)
0136d -55- 04/07/89
-------
Price, K.S., G.T. Uaggy and R.A. Conway. 1974. Brine shrimp bloassay and
seawater BOD of petrochemicals. J. Water Pollut. Control Fed. 46: 63-77.
*« *
Raj an, N., R. Rahlm and S. Krishna Kumar. 1985. Formic add poisoning with
suicidal Intent: A report of 53 cases. Postgrad Med. J. 61(711): 35-36.
*"
Rosewarne, F.A. 1983. Self poisoning with formic add [letter].
Anaesthesia. 38(110): 1104-1105.
SANSS (Structure and Nomenclature Search System). 1988. Chemical Informa-
tion System (CIS) computer data base. On-line: May 5, 1988.
Sax, N.I. 1984. Dangerous Properties of Industrial Materials, 6th ed. Vatr-
Nostrand Relnhold Co., New York. p. 1453.
Schafer, E.W., Jr., W.A. Bowles, Jr. and J. Hurlbut. 1983. The acute oral
toxldty, repellency, and hazard potential of 998 chemicals to one or more
species of wild and domestic birds. Arch. Environ. Cont. Toxlcol. 12(3):
355-382.
Schotten. 1883. Ueber die fluchtlgen Savren des Pferdeharns und das
Verholten der fluchten Fettauven In Organlsmus. Chem. 7: 375. (Cited In
von Oettlngen, 1959)
Schultz, L. 1883. No title provided. Arch. Exper. Path. U. Pharmakol.
16: 305. (Cited 1n von Oettlngen, 1959)
0136d -56- 04/07/89
-------
Slgurdsson, J., A. Bjornsson and S.T. Gudmundsson. 1983. Formic acid burn
Local and systemic effects. Report of a case. Burns Incl. Therm. InJ.
9(5): 358-361.
Solmann, T. 1921. Studies of chronic Intoxication of albino rats. III.
Acetic and formic acids. J. Pharmacol. Exp. Ther. 16:1.463-474.
Speece, R.E. 1983. Anaerobic biotechnology for Industrial wastewater
treatment. Environ. Sc1. Technol. 17: 416A-427A.
Sperling, F., E.S. Maxwell and VI.F. von Oettlngen. 1953. Comparative
excretion and distribution of C14-labeled carbonate and formate 1n large
albino rats. Am. J. Physlol. 174: 33-38. (Cited 1n Tracor-Oltco, 1974)
Sporn, A., V. Paris and M.V. Shoebesch. 1962. Toxldty of formic add.
Iglena, Bucharest. 11: 507-515. (Cited In Tracor-JHco, 1974)
SRI (Stanford Research Institute). 1987. 1987 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
p. 681.
Stern, M. 1906. Sixteen years of experience with formic acid as a thera-
peutic agent. J. Am. Med. Assoc. 46: 1258-1262. (Cited In Tracor-JHco,
1974)
Stumm-Tegethoff, B.F.A. 1969. Formaldehyde-Induced mutations In DrosophUa
melanogaster In dependence of the presence of adds. Ther. Appl. Genet.
39: 330-334.
0136d -57- 04/07/89
-------
Takemoto, S., Y. Kuge and M. Nakamoto. 1981. The measurement of BOD In sea
water. Su1sh1tsu Odaku Kenkyu. 4: 80-90.
Thomas, R.G. 1982. Volatilization fro"m water. In.: Handbook of Chemical
Property Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed.
McGraw H111 Book Co.1, New York! p. 15-1 to 15-34. '" '''
*> -i - -' ' /
Tracor-Jltco. 1974. Scientific Literature Reviews on Generally Recognized
as Safe (GRAS) Food Ingredients - Formic Acid and Derivatives. NTIS
PB228-558.
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria^-
Documents.^ Federal Register. 45(231): 79347-79357.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxlclty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Integrated Risk Information System (IRIS): Reference Dose
(RfD) for Oral Exposure for Formic Add. Online. (Verification date
8/19/85). Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
0136d -58- 04/07/89
-------
U.S. EPA. 1986b. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OM for the Office of Solid Waste, Washington,
DC. .
. * '
U.S. EPA. 1988. Integrated Risk Information Syslem (IRIS). Online.
Chemical File for Formic Add. Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S.- -ffA/OWRS (Office of Water Regulations and Standards). 1986. Guide-
lines for Deriving Numerical Water Quality Criteria for the Protection of
Aquatic Organisms and Their Uses. Office of Research and Development^
Washington, DC. NTIS PB85-227049/XAB.
U.S. FDA (Food and Drug Administration). 1976. Evaluation of the Health
Aspects of Formic Add, Sodium Formate, and Ethyl Formate as Food Ingre-
dients. FDA Contract #223-75-2004, prepared for the U.S. FDA, Washington,
DC.
U.S. FDA (Food and Drug Administration). 1980. Affirmation of GRAS Status
for Ethyl Formate, Formic Add, and Sodium Formate as Direct and Indirect
Human Food Ingredients. Federal Register. 45(67): 22914-22915.
U.S. FDA (Food and Drug Administration). 1988. Part 186 - Indirect Food
Substances Affirmed as Generally Recognized as Safe. 21 CFR 186.1, 21 CFR
186.1316.
0136d -59- 08/15/89
-------
von Oettlngen, W.F. 1959. The aliphatic acids and their esters - Toxlclty
and potential dangers. Am. Hed. Assoc. Arch. Ind. Health. 20: 517-531.
Wagner, F.S. 1980. Formic acid and derivatives {formic add). In: K1rk-
Othmer Encyclopedia of Chemical Technology, Vol. 11, 3rd ed., M. Grayson and
D. Eckroth, Ed. John Wiley and Sons, Inc., New York. p. 251-258.
Weast, R.C. 1985. CRC Handbook of Chemistry and Physics, 66th ed. CRC
Press, Inc., Boca Raton, FL. p. 162.
Welngarten, R. 1932. No title provided. Hed. Wchnschr. 79: 1043. (CHed
1n von Oettlngen, 1959)
W1ld1sh, D.J., H. Akagl and N.J. Poole. 1977. Avoidance by herring of
dissolved components In pulp mill effluents. Bull. Environ. Cont. Toxlcol.
18(5): 521-525.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Rahway,
NJ. p. 605.
0136d -60- 04/07/89
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APPENDIX A
.LITERATURE SEARCHED ,
* *
This HEED Is based on data Identified by computerized literature
searches of the following:
*
CHEMLINE
TSCATS ' . . ,
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases .. - , .. -
SANSS . . '
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted In Hay, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0136d -61- 04/07/89
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Clayton, 6.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
Grayson, H. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed,. John Wiley, and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk *t>f Chemicals to
Humans. IARC, WHO, Lyons, France. ,. : r. .,/...
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA. ;
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892. Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0136d -62- 04/07/89
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the Following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC. f
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates! Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Oept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic -
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0136d -63- 04/07/89
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to
o<
Q.
APPENDIX B
Summary Table for formic Acid
I
a*
Species
Inhalation Exposure
Subchronlc ID
Chronic ID
Carcinogenic I ty 10
Oral Exposure
Subchronlc rat
Chronic rat
Carcinogenic Ity ID
gtPORTABy_9yAjT ini s
Based on chronic toxic Ity:
Based on carclnogenlclty:
Exposure
ID
ID
ID
150-200 mq calcliM formate/
kg/day In Miltlgeneratlon
study (200 ag/kg/day dosage
equivalent to foratc acid
at 141 ag/kg/day)
150-200 ag ca Ideal formate/
kg/day In Miltlgeneratlon
study (200 ag/kg/day dosage
equivalent to formic acid
at 141 ag/kg/day)
ID
1000
NO
Effect RfD or q|* Reference
*
ID NO NA
ID NO > NA
ID ND NA
slightly Increased phagocytosis 1 ag/kg/day Nalorny. 19696
In some tissues; no effects on -
reproduction (NOAEL)
t,
slightly Increased phagocytosis 1 ag/kg/day Nalorny. 1969b
In some tissues; no effects on
reproduction (NOAEL)
ID 10 , NA
1 >
Sporn et al., 1962
NA
ID - Insufficient data; NO -- not derived; NA ~ not applicable
oo
ID
-------
.APPENDIX C
DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO FORMIC ACID
C.I. DISCUSSION
Dose/duration-response graphs for oral exposure to formic add generated
by the method of Crockett et al. (1985) using the computer software by
Durkln and Meylan (1988) under contract to ECAO-C1nc1nnat1 are presented In
Figures C-1 and C-2. Data used to generate these graphs are presented 1n
Section C.2. In the generation of these figures all responses are
classified as adverse (PEL, AEL or LOAEL) or nonadverse (NOEL or NOAEL) for
plotting. If data are available for Inhalation exposure: The ordlnate
expresses concentration 1n either of two ways. In flgure(s) {---), the
experimental concentration expressed as mg/m3 was multiplied by the time
parameters of the exposure protocol (e.g., hours/day and days/week) and Is
presented as expanded experimental concentration [expanded exp cone
(mg/m3)]. In f1gure(s) (), the expanded experimental concentration was
multiplied by the cube root of the ratio of the animal :human body weight to
estimate an equivalent human or scaled concentration [scaled cone (mg/m3)]
(U.S. EPA, 1980; Mantel and Schnelderman, 1975).
The boundary for adverse effects (solid line) Is drawn by Identifying
the lowest-adverse-effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point an Infinite
line 1s extended upward parallel to the dose axis. The starting point. 1s
then connected to the lowest-adverse-effect dose or concentration at the
next longer duration of exposure that has an adverse-effect dose or
concentration equal to or lower than the previous one. This process 1s
continued to the lowest-adverse-effect dose or concentration. From this
point a line Is extended to the right parallel to the duration axis. The
region of adverse effects lies above the adverse effects boundary.
0136d -65- 04/07/89
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9
t
H
It
100088 r
IM
9
Z
1800 -r
108
t i iii
iiiiiii
i iiiiiii
0.00001
0.0001 0.001 0.01 0.1
HUNAN EQUIV MIRATION (fraction lifcspan)
"*» ^
\
I '
1 2
Key:
N
n
F
A
o
NOEL
NOAEL
PEL
AEL
NOCEL
FIGURE C-l
Dose/Duration Response Graph - Oral Exposure to
Formic Acid Equivalents Using the Envelope Method
0136d
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1888888
91
01
H
18
188888 T
I
Z
a
z
18888 T
1888 T
188
F
F
o.aaeei
N
4-
8.0001 O.OO1 8.81 8.1
HUMAN EQUIU MIRATION (fraction lifcspan)
1 2
Key:
N
n
F
A
o
NOEL
NOAEL
FEL
AEL
NOCEL
FIGURE C-2
Dose/Duration Response Graph - Oral Exposure to
Formic Add Equivalents Using the Censored Data Method
0136d
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Using the envelope method, the boundary for no adverse effects (dashed
line) 1s drawn by Identifying the highest no-adverse-effects dose or
concentration. From this point a line parallel to the duration axis 1s
extended to the dose or concentration axis. The starting point 1s then
connected to the next highest or equal no-adverse-effect dose or
' -';v'/
concentration at a longer duration of exposure. When this process can no
longer be continued, a line Is dropped parallel to the dose or concentration
axis to the duration axis. The region of no adverse effects lies below the
no-adverse-effects boundary. At both ends of the graph between the
adverse-effects and no-adverse-effects boundaries are regions of ambiguity.
The area (1f any) resulting from Intersection of the adverse-effects and
no-adverse-effects boundaries Is defined as the region of contradiction.
In the censored data method, all no-adverse-effect points located In the"
region of contradiction are dropped from consideration and the
no-adverse-effect boundary 1s redrawn so that 1t does not Intersect the
adverse-effects boundary and no region of contradiction Is generated. This
method results In the most conservative definition of the no-adverse-effects
region.
The data, a total of 15 records. Include several LD~Q values and
effect levels from 1-day to 3-year studies In several species. The three
human studies reported local Irritation or mortality from 1-day exposures.
Little area of contradiction 1s apparent (see Figure C-l). Figure C-2
clearly delineates a boundary for no adverse effects that Is well above the
recommended oral RfO of 1 mg/kg/day (70 mg/day for a 70 kg human).
0136d -68- 04/07/89
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RECORD #3:
Comment:
Citation:
RECORD #4:
Comment:
Citation:
RECORD #5:
Comment:
Citation:
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
1050 value; details not av<
Guest et al., 1982
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
1050; details of study not
NIOSH. 1988
Species: Mice
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Dose:
Duration Exposure:
Duration Observation:
**
Ulable.
% .
Dose:
Duration Exposure:
Duration Observation:
available.
Dose:
Duration Exposure:
Duration Observation:
1830.000
1.0 days
1.0 days
-
.. . . . _ . ..
1100.000
1.0 days
1.0 days
700.000
1.0 days
1.0 days
1050 value; details not available.
NIOSH, 1988
0136d
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RECORD #6:
Comment:
Citation:
RECORD #7:
Comment:
Citation:
RECORD #8:
Comment:
Citation:
Species: Mice Dose:
Sex: NR Duration
Effect: PEL Duration
Route: Oral (NOS)
*i
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: " BODY
Severity Effect: 9
1050 value; details not available.
Malorny. 1969b
Species: Rabbits Dose:
Sex: NR Duration
Effect: FEL Duration
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Details not available.
Guest et al., 1982
Species: Humans Dose:
Sex: NR Duration
Effect: FEL Duration
Route: Oral (NOS)
Number Exposed: 6
Number Responses: 1
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
This level has been Identified as mor
Jefferys and Wiseman, 1980
1100.000
Exposure: 1.0 days
Observation: 1.0 days
4000.000
Exposure: 1.0 days
Observation: 1 .0 days
429.000
Exposure: 1 .0 days
Observation: 1 .0 days
talHy threshold.
0136d
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RECORD #9:
Comment:
Citation:
RECORD #10:
Species: Rats
Sex: Both
Effect: NOCEL
Route: -Water
Number Exposed:
Number Responses
Type of Effect:
SHe of Effect:
Severity Effect:
Unclear whether
Malorny, 1969b
Species: Human
Sex: NR
Effect: AEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
NR "
: NR
CANCR
COLON
3
all organs
s
(NOS)
23
: NR
IRRIT
MOUTH
6
Dose: 200.000
Duration Exposure: 2.0 years
Duration Observation: 2.0 years
NR NR
NR NR
CANCR CANCR
LIVER KIDNY
3 3
and tissues were examined
Dose: 71.400
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
3
NR
IRRIT
COLON
6
Comment:
Citation:
RECORD #11:
Oropharyngeal and gastrointestinal burns are the most
commonly reported effects from oral exposure.
Jefferys
Species:
Sex:
Effect:
Route:
and Wiseman, 1980
Humans
Hale
NOEL
Food
Dose: 8.000
Duration Exposure: 4.0 weeks
Duration Observation: 4.0 weeks
Comment:
Citation:
Number Exposed: NR
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: MOUTH
Severity Effect: 6
Formic acid was administered dally In lemonade. At "higher
dose", "local actions" (presumably burns) were observed.
Lebbln, 1916
0136d
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RECORD #12:
Species:
Sex:
Effect:
Route:
Rats
NR
AEL
Food
Dose: 250.000
Duration Exposure: 6.0 weeks
Duration Observation: 6.0 weeks
Number Exposed: 0
Number Responses: NR
Type of Effect: WGTIN
Site of Effect: BODY
Severity Effect: 3
Comment:
Citation:
RECORD #13:
Slight growth Inhibition, not statistically significant.
Sporn et al., 1962
Species: Rats
Sex: Both
Effect: AEL
Route: Water
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
70
0
HE MAT
BLOOD
3
Dose:
Duration Exposure:
Duration Observation:
70
NR
DEATH
FETUS
9
1400.000
7.0 months
7.0 months
Comment: Endpolnts examined were reproductive performance, hematology,
liver nitrogen content, adrenal ascorbic acid content. 1%
formic add administered continuously for 7 months.
Citation: Sporn et al., 1962
RECORD #14: Species: Rats
Sex: Both
Effect: NOAEL
Route: Water
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
8
NR
FUNR.
TESTE
3
Dose:
Duration Exposure:
Duration Observation:
24 32
NR NR
FUNR WGTIN
OVARY BODY
3 3
200.000
3.0 years
3.0 years
Comment:
Citation:
No reproductive function, growth or organ function effects
noted. Slight changes In lung, spleen, abdominal lymph nodes
could not be attributed to administration of 0.2% calcium
formate 1n water.
Malorny, 1969b
0136d
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RECORD #15;
Comment:
Citation:
Species;
Sex:
Effect:
Route:
Rats
Both
NOAEL
Water
Number Exposed:
Number Responses;
Type of Effect:
Site of Effect:
Severity Effect:
fi
NR
NR
HISTO
BODY
3
Dose: 400.000
Duration Exposure: 2.0 years
Duration Observation: 2.0 years
300-400 mg/kg/day (0.4% calcium formate In drinking water
Induced no hlstopathologlc lesions. No further details
reported.
Malorny, 1969b
NR = Not reported
0136d
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