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                                  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

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                                    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

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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.

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    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

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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.

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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).

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                              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

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                          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

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                           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

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                             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

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    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

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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

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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

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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

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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

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                                 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

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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

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    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

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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

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                         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

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    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

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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

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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

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                               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

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                                   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

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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

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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

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                    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

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                                  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

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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

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    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

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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

-------
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

-------
                             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

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                           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

-------
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                                                       *> -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

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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

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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

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                                  .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

-------
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
                                       -66-
                                                                            04/07/89

-------
   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
                                          -67-
                                                                           04/07/89

-------
    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

-------

-------
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
-70-
04/07/89

-------
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
-71-
04/07/89

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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
                     -72-
04/07/89

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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
                     -73-
                                           04/07/89

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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
                     -74-
                                           04/07/89

-------