EPA-540/1-86-011
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                      Superfund
&EPA
                       HEALTH EFFECTS ASSESSMENT
                       FOR  CYANIDE

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                                           EPA/540/1-86-011
                                           September 1984
       HEALTH EFFECTS  ASSESSMENT
               FOR CYANIDE
    U.S. Environmental Protection  Agency
     Office of Research and Development
Office of Health  and  Environmental Assessment
Environmental Criteria and Assessment  Office
            Cincinnati,  OH   45268
    U.S. Environmental Protection  Agency
  Office of Emergency  and  Remedial Response
Office of  Solid Waste and Emergency  Response
            Washington,  DC  20460

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                                  DISCLAIMER

    This  report  has  been  funded  wholly  or  1n  part by  the  United  States
Environmental  Protection  Agency  under  Contract  No.  68-03-3112  to  Syracuse
Research Corporation.  It has been  subject  to  the Agency's peer and adminis-
trative review, and  H has  been  approved  for  publication as an EPA document.
Mention of  trade  names or  commercial  products  does  not  constitute  endorse-
ment or recommendation for use.
                                      11

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                                    PREFACE


    This report  summarizes  and evaluates Information relevant  to  a prelimi-
nary  Interim  assessment of adverse  health  effects associated  with cyanide.
All  estimates  of acceptable  Intakes and  carcinogenic  potency  presented  1n
this  document  should be  considered  as  preliminary  and reflect  limited  re-
sources allocated to this project.  Pertinent  toxlcologlc  and  environmental
data  were  located   through   on-Hne  literature   searches  of  the  Chemical
Abstracts,  TOXLINE,  CANCERLINE  and  the CHEMFATE/DATALOG  data bases.   The
basic   literature  searched   supporting   this   document  Is  current  up   to
September,  1984.   Secondary  sources of  Information have  also been  relied
upon  1n the  preparation of  this  report and  represent  large-scale  health
assessment  efforts   that  entail   extensive  peer  and  Agency  review.   The
following Office  of  Health and Environmental Assessment  (OHEA)  sources  have
been extensively utilized:


    U.S.  EPA.    1980a.   Ambient  Water   Quality  Criteria  for  Cyanides,
    with Errata  for  Ambient Water  Quality Criteria Documents  dated June
    9,  1981  {Updated:  February  23,  1982).  Prepared  by  the  Environ-
    mental Criteria  and  Assessment  Office,  Cincinnati,  OH,  OHEA for the
    Office  of  Water  Regulations  and Standards, Criteria  and Standards
    Division, Washington, DC.   EPA 440/5-80-037.  NTIS PB 81-117483.

    U.S.  EPA.    1985.    Drinking  Water  Criteria  Document  on  Cyanide.
    Prepared  by  the  Environmental  Criteria  and  Assessment  Office,
    Cincinnati,  OH,  OHEA for  the Office  of  Drinking  Water, Washington,
    DC.  Final draft.


    The Intent 1n these  assessments  1s  to suggest  acceptable  exposure levels
whenever  sufficient  data were available.  Values were  not  derived or larger
uncertainty  factors  were  employed  when  the variable  data were  limited  In
scope  tending  to generate conservative (I.e.,  protective) estimates.  Never-
theless,  the  Interim values  presented reflect  the relative degree of hazard
associated with exposure or risk to  the chemlcal(s) addressed.

    Whenever possible,  two categories  of values have  been estimated for  sys-
temic  toxicants  (toxicants for  which cancer  1s  not the endpolnt of concern).
The  first,  the  AIS  or  acceptable  Intake subchronlc,  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 lifespan).   This  type  of
exposure  estimate has  not  been extensively used  or rigorously  defined,  as
previous  risk  assessment  efforts  have  been  primarily  directed  towards
exposures from toxicants 1n ambient air  or  water  where lifetime exposure 1s
assumed.   Animal data  used  for  AIS  estimates generally  Include exposures
with  durations  of 30-90  days.   Subchronlc  human data  are  rarely available.
Reported  exposures are usually from chronic occupational  exposure situations
or  from reports of acute accidental  exposure.
                                      111

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    The  AIC,  acceptable  Intake  chronic, 1s  similar 1n  concept  to  the  ADI
(acceptable  dally  Intake).   It  Is  an  estimate  of an  exposure  level  that
would  not  be expected  to cause  adverse effects  when  exposure occurs  for  a
significant portion  of  the Hfespan  [see U.S.  EPA  (1980b) for a  discussion
of  this   concept].   The  AIC  Is  route specific  and  estimates   acceptable
exposure  for  a given  route with  the  Implicit  assumption that exposure  by
other routes 1s Insignificant.

    Composite  scores  (CSs)  for  noncardnogens  have  also  been   calculated
where data  permitted.   These  values  are used for  ranking  reportable  quanti-
ties; the methodology for their development  Is explained  1n U.S. EPA (1983).

    For compounds for which there  1s  sufficient  evidence  of  cardnogenlcHy,
AIS  and  AIC values  are  not derived.   For  a  discussion  of risk  assessment
methodology  for  carcinogens  refer  to U.S.  EPA  (1980b).   Since cancer  1s  a
process  that  Is  not  characterized by  a threshold,  any exposure  contributes
an Increment of  risk.   Consequently,  derivation of  AIS and AIC values  would
be Inappropriate.   For  carcinogens,  q-]*s  have been computed  based  on  oral
and Inhalation data 1f available.
                                      iv

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                                   ABSTRACT


    In  order  to  place the  risk  assessment  evaluation  1n  proper  context,
refer  to  the preface  of   this  document.   The  preface outlines  limitations
applicable to all documents of  this  series as  well  as the appropriate inter-
pretation and use of the quantitative estimates presented.

    Adequate data  are  available  for  experimental  animals orally  exposed  to
cyanide.   The  various  studies  agree  well in  terms  of  suggesting  a  NOEL.
U.S.  EPA  (1985)  has  calculated  a  NOEL  of  10.8 mg  CN~/kg  for female  rats
exposed to cyanide  1n  their  food as a  basis  for  estimating  acceptable expo-
sure  levels  (Howard and Hanzel,  1955).   The  AIC  based on this  study is  1.5
mg/man/day.  A  CS  of  14.4  was calculated  for  the  effects of degeneration  of
ganglion cells in the CNS  observed 1n dogs treated with NaCN  by capsule.

    Data  for  effects  following  inhalation  exposure to  CN'  are  extremely
limited.  An  AIC has  been estimated based on  the TLV of  5  mg/m3  but should
not be  adopted  because of presumed  greater  toxidty due  to exposure by  the
inhalation route.

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                               ACKNOWLEDGEMENTS
    The  Initial  draft  of  this  report  was  prepared  by Syracuse  Research
Corporation under  Contract No.  68-03-3112  for EPA's  Environmental  Criteria
and  Assessment  Office,  Cincinnati,  OH.   Dr.  Christopher  DeRosa and  Karen
Blackburn were the Technical Project Monitors  and  Helen Ball  was^the Project
Officer.  The final documents  1n  this  series  were  prepared  for the Office of
Emergency and Remedial Response, Washington, DC.

    Scientists from  the  following U.S. EPA offices  provided  review  comments
for this document series:

         Environmental Criteria and Assessment Office, Cincinnati, OH
         Carcinogen Assessment Group
         Office of A1r Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document series was provided by:

    Judith Olsen and Erma Durden
    Environmental Criteria and Assessment Office
    Cincinnati, OH

Technical support services for the document series  was provided by:

    Bette Zwayer. Pat Daunt, Karen Mann and Jacky Bohanon
    Environmental Criteria and Assessment Office
    Cincinnati, OH
                                      vl

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TABLE OF CONTENTS

1.
2.


3.










4.








5.


ENVIRONMENTAL CHEMISTRY AND FATE 	 • 	 ,
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . .
2.1.
2.2.
ORAL 	 ,
INHALATION 	
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1.


3.2.


3.3.


3.4.
SUBCHRONIC 	 ,
3.1.1. Oral 	
3.1.2. Inhalation 	 ,
CHRONIC 	
3.2.1. Oral 	
3.2.2. Inhalation 	 ,
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 	
3.3.1. Oral 	
3.3.2. Inhalation 	 ,
TOXICANT INTERACTIONS 	
CARCINOGENICITY 	
4.1.


4.2.


4.3.
4.4.
HUMAN DATA 	
4.1.1. Oral 	
4.1.2. Inhalation 	
BIOASSAYS 	 ,
4.2.1. Oral 	 ,
4.2.2. Inhalation 	 ,
OTHER RELEVANT DATA 	 ,
WEIGHT OF EVIDENCE 	
REGULATORY STANDARDS AND CRITERIA 	
Page
1
. , , 4
. . . 4
4
6
. . . 6
. . . 6
, , , 9
11
. . . 11
11
13
. . . 13
. , , 13
. . . 13
. . , 15
. . . 15
. . . 15
. . . 15
. . . 15
. . . 15
. . . 15
. . . 15
. . . 16
. . . 17
       V11

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                           TABLE  OF  CONTENTS  (cont.)

                                                                        Page

 6.  RISK ASSESSMENT	   19

     6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS) 	   19

            6.1.1.   Oral	   19
            6.1.2.   Inhalation	   19

     6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)	   19

            6.2.1.   Oral	   19
            6.2.2.   Inhalation	   22

     6.3.   CARCINOGENIC POTENCY (q-|*) 	   22

            6.3.1.   Oral	   22
            6.3.2.   Inhalation	   22

 7.  REFERENCES	   23

APPENDIX: Summary Table for Cyanide	   33

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                               LIST OF TABLES

No.                               Title                                Page

1-1     Selected Physical and Chemical Properties  of a
        Few Cyanides	     2

3-1     Subchronlc Toxldty of Orally Administered Cyanide	     7

3-2     Representative Control Studies of Occupational
        Exposure to Cyanide by Inhalation or Dermal Routes	    10

3-3     Chronic Toxldty of Orally Administered Cyanide	    12

5-1     Tolerance for  Hydrogen Cyanide 1n Foodstuffs When Used
        as a Post-Harvest Fumlgant	    18
                                     1x

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                             LIST OF ABBREVIATIONS

ADI                     Acceptable dally Intake
AIC                     Acceptable Intake chronic
AIS                     Acceptable Intake subchronlc
BCF                     B1oconcentrat1on factor
bw                      Body weight
CNS                     Central nervous system
CS                      Composite score
EKG                     Electrocardiogram
GI                      Gastrointestinal
LDso                    Median lethal dose
NOAEL                   No-observed-adverse-effect level
NOEL                    No-observed-effect level
RVg;                 •    Dose-rating value
RVe                     Effect-rating value
TLV                     Threshold limit value
TWA                     Time-weighted average
UF                      Uncertainty factor

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                     1.  ENVIRONMENTAL CHEMISTRY AND FATE



    The  relevant  physical  and  chemical  properties of  selected  cyanides  are

given In Table 1-1.

    The  fate  of  cyanides  1n  the  aquatic media  may vary  widely.   Hydrogen

cyanide  and the  common alkali metal cyanides may  be lost from aquatic media

primarily  through  the volatilization  process  (Callahan et al.,  1979).   The

predominant fate  processes  for sparingly  soluble  metal  cyanides,  such  as

copper  cyanide,  are expected  to  be sedimentation and  mlcroblal  degradation

(Callahan  et  al.,  1979).   The water-soluble complex metal  cyanides,  such  as

ferrocyanlde  and  ferrlcyanldes, may  undergo  some  photodecompos1t1on.   In  the

absence  of such  destabilizing  factors   1n  water  as   high temperature  and

extreme  pH condition,  these  complexes are expected  to have  long  lifetimes

and  may undergo  substantial  transport  1n  aquatic  media  (Callahan  et  al.,

1979).

    Most  cyanide   1n   the  atmosphere  Is  likely  to  be  present  as  hydrogen

cyanide  gas,  but  small amounts of metal  cyanides  may  be present  as partlcu-

late  matter 1n  the air.   Hydrogen  cyanide slowly reacts  with  hydroxy radi-

cals  1n  the air according to the following reaction (Graedel,  1978):

                              OH.           02
                         HCN  -»  H20 -h CN. -»  CO 4- NO


    Assuming  that  the rate  constant  for  the  above   reaction  1s  2xlO~15

cm3   molecule"1   sec"1  (Graedel,   1978)   and   that   the  OH'   concentration

1s  106  molecules  cm"3,  the  half-life for this  reaction can be  calculated

to  be  -11  years.   Therefore,  1t  appears  that   cyanides  do  not  have  any

significant chemical  loss  mechanism  In  the troposphere.   Physical  transfer

mechanisms,  such  as   wet  and  dry  deposition,  may dominate  the  fate  of

cyanides In the atmosphere.


                                      -1-

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                                                 TABLE 1-1



                        Selected  Physical  and  Chemical  Properties of a Few Cyanides3
Compound
HCN
NaCN
KCN
K3Fe(CN)6
Molecular
Weight
27.03
49.01
65.12
329.26
Chemical
Class
Inorganic
cyanide
Inorganic
cyanide
Inorganic
cyanide
Inorganic
cyanide
Vapor
Pressure
(mm Hgl)
807.2 at
27.2°C
0.76 at
800°C
NA
NA at 4°C
Water
Solubility
completely
mlsclble
48 g/100 mil
at 10°C
71.6 g/100 g
at 25°C
33 g/100 mil
Log Kow BCF
0.66b 1.9C
0.44d 0.27C
NA NA
NA NA
aSources: Weast, 1980; Towlll et al.,  1978 (unless  otherwise  stated)



^Calculated average of values from Leo et  al.,  1971



cCalculated from the equation of Velth et  al.,  1979



^Calculated by the method of Leo et al., 1971,  from the  value given by  Hansch  and  Leo,  1979



NA = Not available

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    The fate of  cyanides  1n soil has been  Inadequately  studied.   By drawing
an analogy  from Its  expected  fate  1n  water,  H  can  be predicted  that  the
fate of cyanides  1n  soil  may be pH  dependent.   In  acidic  soils,  the loss  of
hydrogen cyanide  through  volatilization may be  the  predominant  mechanism  of
loss from  soil  surfaces.    In subsurface  soil,  cyanides that are  present  1n
small concentrations  (below the toxic  levels for  microorganism)  may undergo
some microblal degradation  (Callahan  et al.,  1979);  1n  addition,  considering
cyanide's low soil sorptlon  characteristics  (Callahan et al.,  1979)  and high
water solubility, some  may  leach through  the soil.   In  spite  of  this expec-
tation, cyanides have  rarely been  detected In groundwater.  In  basic soils,
the mobility of cyanides In soil 1s expected to be greatly  restricted.
    The simple metal  cyanides and  hydrogen cyanide  are  not  expected to bio-
accumulate In aquatic  organisms  (U.S. EPA, 1980a).  The water  soluble metal
cyanide  complexes,  however,  may  bloaccumulate   to  some  extent   In  aquatic
organisms  although  the bloaccumulatlon factors   for  such  compounds  are  not
known (Callahan et al., 1979).
                                      -3-

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           2.   ABSORPTION FACTORS IN HUMANS AND  EXPERIMENTAL  ANIMALS
2.1.   ORAL
    Cyanide 1s  readily absorbed by  the  GI tract.  Gettler  and  Balne (1938)
exposed dogs to potassium  cyanide  equivalent  to 1.57,  4.42 or 8.42 mg HCN/kg
bw by gavage.  Upon  death  (155,  21  and 8 minutes post-treatment), the amount
of potassium  cyanide remaining  1n  the GI tract was measured and subtracted
from  the  amount administered;  this was  considered  to be equivalent  to  the
amount absorbed, and  was 72,  24 and  16.6% for  dogs  receiving 1.57,  4.42  and
8.42 mg/kg, respectively.
    Yamamoto et al.  (1982) exposed  rats  orally by gavage to  either  7  or  21
mg  NaCN/kg bw.  Following treatment  and  subsequent  death  (minutes  later),
levels  of  cyanide   1n   the  blood  were  5.01+1.61  and  4.79+2.04 yg/mi  for
the  low  dose  and  high  dose,  respectively.   This   Indicates   that  sodium
cyanide was absorbed readily by the GI tract.
    The  U.S.  EPA  (1980a)   reported  that  hydrogen  cyanide  1s more  rapidly
absorbed  than  cyanide salts,  because  H  1s a  weak add with a  pKa  of 9.2.
At  physiological  stomach  pH,  HCN  occurs  predominantly  1n   the  non-1on1zed
form; hence, absorption 1s facilitated.
2.2.   INHALATION
    Studies  Involving  both animals  and  humans  Indicate  that  cyanide   1s
absorbed  readily by  Inhalation.   Dogs exposed  to hydrogen cyanide through  a
breathing  tube absorbed  1.11-1.55  mg/kg bw and died within  10-15 minutes  of
exposure  (Gettler   and  Balne,   1938);   however,  doses  were  not reported.
Knowles and Bain (1968)  demonstrated a correlation between  levels of  hydro-
gen  cyanide  1n the  air and 1n  human blood.   Individuals exposed to  >300,
>200, >100 or >50  ppm  had  levels  of  cyanide  1n  blood equivalent  to >10,
                                      -4-

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8-10, 3-10  or  2-4 mg/a, respectively.   Landahl  and Herrmann  (1950)  report-
ed  that  humans  retained  60% of  the administered  dose  of hydrogen  cyanide
Inhaled by mouth.
    Absorption  of  cyanide  from  smoke  Inhaled  by  cigarette  smokers  1s
Inferred by  the  plasma levels of  thlocyanate  1n smokers  compared  with  non-
smokers.  Although  significant  differences  In  the  plasma levels of  cyanide
were not found between  the  two groups,  the  level  of thlocyanate was signifi-
cantly higher 1n  smokers, a  reflection  not  only  of  the absorption of  cyanide
from Inahled cigarette  smoke but also of  Us  rapid  metabolism to thlocyanate
(Wilson and Matthews, 1966).
                                      -5-

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                3.  TOXICITY  IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.      In  evaluating   studies  regarding  the  oral   toxldty  of
cyanide,  factors affecting the rate of absorption may  be as  Important as  the
dose administered  (U.S.  EPA, 1985).  Cyanide  1s  metabolized rapidly  by  the
liver  to  thlocyanate,  an  enzymatic rate-saturable  reaction.   Factors  that
enhance absorption  may  result  In  severe  toxic manifestations  from a  dose
that ordinarily  would  not cause  toxldty,  because  the  ability of  the  Hver
to  metabolize  cyanide  as  a first  pass  phenomenon  had  been exceeded.   The
volume of  the  Intestinal contents  and rate  of peristalsis  are  factors  that
affect the  rate of  GI absorption.  It  may also be expected that  toxldty
would be more likely 1f  cyanides  are given  as  a bolus  rather than 1n smaller
allquots  throughout the day.
    Another Important  consideration regarding  dietary  studies  1s  the propen-
sity for .cyanide to  volatilize  from treated foodstuffs,  resulting  1n a  lack
of  toxic  manifestations   at  potentially  dangerous  levels (U.S.   EPA,  1985).
Also,  animals   (and  presumably  humans)   can  successfully  withstand  higher
doses  of  cyanide when administered 1n  the  diet  rather  than by  Inhalation,
because of the  first pass conversion of  orally administered  cyanide to thlo-
cyanate (detoxification)  1n the liver.
    Data   regarding  the  subchronlc  toxldty of  orally  administered  cyanide
are summarized  In Table  3-1.  Palmer and Olson (1979)  reported  significantly
higher liver weights  1n  adult rats  exposed  to 200  mg  KCN/9. drinking water,
but no effect on Hver weight when  potassium cyanide was administered as  200
mg/kg  diet.   Tewe  (1982) and  Tewe and  Maner  (1980,  1982)  treated  weanling
pigs  and  rats  with potassium cyanide, and  observed only a  slight  reduction
1n  food consumption with  no  other  effects.   Hayes  (1967) reported that adult
                                      -6-

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                                                                   TABLE 3-1

                                               Subchronlc Toxlclty of Orally Administered Cyanide
Species/ Number/Sex
Height or Age
Rat/70 g 7 H/group
7 N/group
Rat/adult MR
NR

Rat/weanling 8 N and F/
group
African giant rat/ 6 N and 2
wean11ng/~90 g F /group
Pig/weanling 1 N, 1 F
Dose of Compound
0 and 200 mg
KCN/t
drinking water
0 and 200 mg
KCN/kg diet
0. 10 mg KCN/kg
bw/day In diet
0-250 mg KCN/kg
bw/day In diet

0. 1875 mg
KCN/kg diet
0. 2500 mg
KCN/kg diet
0. 1875 mg
KCN/kg diet
Dose as CNa
0 and 80 mg/l
(8 mg/kg bw/day)
0 and 80 mg/kg
diet (4 mg/kg
bw/day)
0. 4 mg/kg
bw/day
0-100 mg/kg
bw/day

0, 750 mg/kg
diet (37.5
mg/kg bw/day)
0, 1000 mg/kg
diet (36 mg/kg
bw/day )b
0, 750 mg/kg
d1et(~30 mg/kg
bw/day )b
Period of
Exposure
21 days
21 days
25 days
90 days

56 days
84 days
56 days
Effects
Treated animals: significantly
Increased (p<0.05) liver weights
(15.8 g), compared with controls
(13.5 g). No effect on body weight.
Treated animals: no Increase In
liver weights (13.7 g). compared
with controls (13.5 g). No effect
on body weight.
No mortality.
No mortality; this dose was 25
times the acute oral 1059 for rats.
Animals tolerated CN~ better when
It was mixed 1n feed.
No effect on body weight, ratio of
liver and kidney weight to body
weight, food consumption or protein
efficiency ratio.
Treated animals: slight reduction
In food consumption and weight gain
compared with controls. No hlsto-
pathologlcal changes In spleen,
liver, kidney or thymus.
Treated animals: small but signifi-
cant reduction In food consumption
(p<0.05), compared with controls.
Reference
Palmer and
Olson, 1979

Hayes. 1967


Tewe and
Haner, 1982
Tewe. 1982
Tewe and
Naner. 1980
Dog/7.6 kg
1 control,
3 treated
(sex NR)
0, 500 ppm NaCN
In diet
3 mg/kg bw/day
30-32 days
No effect on body weight, food
efficiency ratio, protein efficiency
ratio, or ratio of various organ
weights (spleen, liver, kidney,
heart, thyroid) to body weight.  No
hlstopathologlcal changes.

No effects on food consumption,
body weight gain, hematology,
gross or microscopic pathology
American
Cyanamld
Co., 1959

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                                                                        TABLE 3-1  (cont.)
Species/
Weight or Age
Dog/NR
Number/Sex
1 control.
3 treated
(sex NR)
Dose of Compound
NaCN at 0. 0.5,
1.0 up to 2x2.0
mg/kg bw/day by
capsule
Dose as CN*
0. 0.27. 0.53 up
to 2x1.1 mg/kg
bw/day (average
3 mg/kg bw/day
In high group)
Period of
Exposure
15 months
Effects
Toxlclty observed In high group:
acute toxlclty Immediately after
dosing, full recovery In <0.5 hours.
All treated dogs: degeneration of
ganglion and Purklnje cells of CNS.
Reference
Meriting
et al.. 1960
         aValues In parentheses were calculated as follows:
          1) For CN- In the diet, the dose In mg/kg/dlet Is multiplied by the fraction of bw consumed by a rat/day (0.05).
          2) For CN-  In the  water,  the dose  In mg/l  Is  multiplied by  the  average amount  of H?0  consumed  by a  rat/day  (0.035 I/day), and  divided
             by  the  weight of  the  rat  (If unknown.  It  Is assumed to be 0.35  kg),  e.g..  rats assumed to drink  water  equivalent to 10% of  their  body
             weight/day.
         ^Calculated by U.S.  EPA  (1985) from body weight and food consumption data provided by Investigators.
         NR - Not reported
i
oo
i

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rats  could  tolerate  25  times  the  LD5Q  dose  of potassium  cyanide when  It
was administered  1n  the  diet.  When given  1n  the diet, NaCN at  3  mg  CN~/kg
bw/day had no effect  1n  dogs  (American  Cyanamld  Co.,  1959).   The same  dosage
given by  capsule  led  to  signs of acute  toxldty  1n dogs  from which recovery
was  complete within  0.5  hours  (Herttlng et  al.,  1960).   When  given  by
capsule  to  dogs  for  15  months,  3 mg CN~/kg  bw/day was sufficient  to  cause
cellular  degeneration 1n  the  CNS.   Although  animals  1n  this  study  were
exposed  to  a range of potassium  cyanide  concentrations,  these  Investigators
only reported mortality.
3.1.2.   Inhalation.   Only   one  animal   study   regarding  the  subchronlc
toxldty  of  cyanide  was  located  1n  the available  literature.   Hugod  (1981)
exposed  rabbits  (22/group)  to  either   0  or 0.55 mg/m3 hydrogen cyanide  1n
air.  After 28 days,  the treated  animals  were  not different  from controls  In
myocardlal ultrastructure.
    In humans, exposure  to cyanide  by  Inhalation and  dermal  routes has  been
reported  1n- the metal  Industry.   Sandberg  (1967)  reported  on  a  goldsmith
apprentice  who  polished  gold  5-10  times/day for  4  years.   The  polishing
solution he  used was  prepared by adding  15 g  of  potassium cyanide  to  water,
bringing 1t to a boll, then  adding hydrogen  peroxide;  this process  liberated
hydrogen cyanide gas  and  splattered  the  skin.  Symptoms of  toxldty 1n  this
man Included  headache,  Ustlessness, numbness and  partial paralysis of  his
left arm  and  leg,  and partial  loss  of  vision  1n his   left eye.   Other  cases
1n which similar symptoms  have  been  reported  are  summarized  by  NIOSH  (1976).
There have also been  reports  of goiter  associated with occupational exposure
to  cyanide  (Hardy et  al.,  1950).   In  addition, many case-control studies
regarding  exposure to  cyanide  have  been  reported.   Several  of  these  are
summarized 1n Table 3-2.
                                      -9-

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                                                                            TABLE 3-2

                                 Representative Control Studies of Occupational Exposure to Cyanide by Inhalation or Dermal Routes
          Study Population
 Control Population
Period of Exposure    Level of Exposure
                                   Effects
                                       Reference
o
i
         36 male electro-
         platers from 3
         factories, >30
         years of age, all
         nonsmokers
         13 HCN fumlgators
         who had suffered
         acute symptoms of
         HCN poisoning with
         loss of conscious-
         ness

         31 men, 12 women
         In Romanian metal
         galvanizing opera-
         tion
20 males of compar-
able age and socio-
economic status:
non-smokers not
exposed to cyanide
5-15 years
mean concentration
In the breathing
zone: 7.1. 8.9 and
11.5 mg/m* for the
three factories
4 HCN fumlgators who
had not reported
symptoms of acute
HCN poisoning
NR
1-27 years
NR
0.25-16 years
(mean: 5.4 years)
                                               average  exposure
                                               over  5 years:
                                               0.26  mg/m3
Exposed men: headache (29); weak-    El Ghawabl
ness (28); changes In smell and      et al.,  1975
taste (28); giddiness (20); throat
Irritation (16); vomiting (16);
difficulty breathing (16); pre-
cordlal pain (7); difficulty
focusing eyes (3); psychosis (2).
Nonexposed workers had much lower
Incidences of these symptoms.
Exposed workers also had signifi-
cantly higher (p<0.001) hemoglobin
to lymphocyte counts, and signifi-
cantly higher (<0.001) uptake of
1S1I by the thyroid.

13 symptomatic men: high Incidence   Carmelo, 1955
of nervous disorders; precordlal
pain (9); EKG abnormalities (11);
hypertroplc gastritis (11).  4
controls: no stomach or Intestinal
disorders.

Significantly reduced activity       Dlnca et al..
of cytochrome oxldase and other      1972
redox enzymes.
         NR -  Not  reported

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3.2  CHRONIC
3.2.1.  Oral.   Data  pertaining  to  the  chronic  toxldty  of orally  adminis-
tered cyanide are  summarized  1n Table  3-3.   Howard  and Hanzal  (1955) exposed
rats to  0,  76,  or  190 mg HCN/kg  diet  (equivalent to 0, 73, 183  mg  CITVkg)
for  104 weeks.   None  of  the  animals treated  at   any  level   had   signs  of
toxldty; no  hlstopathologlcal  changes 1n  the heart, lungs,  liver, spleen,
stomach,  Intestines,   kidney,    adrenals,   thyroid,  reproductive   organs,
cerebellum  or  cerebrum;  and no  differences  1n  growth  rate  compared  with
controls.   The  only  effects  of  treatment  were  elevated  levels  of  CN"1  1n
the erythrocytes and elevated thlocyanate  1n the blood, liver and  kidneys.
    Ph1lbr1ck et al.  (1979)   treated groups  of 10 male weanling  rats  with  0
or 1500  mg  KCN/kg  diet and reported signs  of  primary myelln degeneration  1n
the spinal  cord  after  11.5  months treatment.  Rats  maintained  on methlonlne
and vitamin  B,? deficient diet appeared to be affected more seferely.
    With respect to  humans,   the  high  Incidence  of   amblyoplas, thyroid  dis-
orders and  neuropathies  seen  1n tropical  regions of  Africa  has been associ-
ated with chronic  1ngest1on of  cassava, a  dietary staple  containing  a cyano-
genlc  glycoslde  that  releases   hydrogen  cyanide  when metabolized  j_n  vivo
(Monekosso and WHson,  1966;  Osuntokun,  1968,  1972;  Osuntokun et al.,  1969,
1970; MacKenzle  and  Phillips, 1968;  Makene and Wilson, 1972;  Ermans et  al.,
1972;  Delange  and  Ermans,   1971).   Sufficient  data  to   quantify  dose and
effects were not available 1n these studies.
3.2.2.   Inhalation.   Animal  studies  pertaining  to   the chronic  toxldty of
Inhaled  cyanide  could  not  be located 1n the available  literature.   Exposure
to  cyanide  In  tobacco  smoke,  however,  has  been   associated  with  tobacco
amblyopla,  Leber's hereditary optic atrophy, retrobulbar   neuritis and  optic
atrophy  (Wokes,  1958;  Pettlgrew and Fell,  1972,  1973; Wilson  and Matthews,
                                     -11-

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                                                     TABLE 3-3



                                  Chronic Toxldty of Orally Administered Cyanide
ro
Species/
Starting
Weight
Rat/57 g



Weanling
rat/43 g





Number

10 F
and
10 M/
group
10 H/
group




Dose of
Compound

0, 76,
190 mg
HCN/kg
diet
0, 1500
mg diet





Dose as CN~

0, 73, 183
mg/kg diet


0, 600 mg/kg
diet

(0.30 mg/kg
bw/day)*

Period
of
Exposure
104
weeks


11.5
months





Effects

No effects with regard to
body weights or hlsto-
pathologlcal changes of
many organs.
Treated rats: primary
myelln degeneraton and
vacuoles 1n spinal cord.
Decreased plasma thyroxln
levels at 4 months with
recovery by 11 months.

Reference

Howard and
Hanzal, 1955


Phllbrlck
et al., 1979




    *Assum1ng rats eat food equivalent to 5% of  their  body weight/day.

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1966; Foulds et al., 1968; WHson, 1983).  These disorders  Involve  defective



cyanide metabolism (the conversion of cyanide to thlocyanate by  rhodanase  Is



defective) and vitamin  B,? deficiency.



3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE  EFFECTS



3.3.1.   Oral.  The  reproductive  performance  of   rats  fed  500 mg  CN~/kg



diet  throughout  gestation  and  lactation  was  unaffected  (Tewe  and Maner,



1981a).   Furthermore,  Utter  size,  weight of  the pups  at  birth,  and  food



consumption  and  growth  rate  of  pups  after birth were  not  significantly



different from controls.



    In  contrast,   the  fetuses  of  pigs  (9/level)  fed   276.6  or  520.7  mg



CN'/kg  diet  throughout  gestation  to  lactation had  reduced organ  to  body



weight ratios for thyroid, heart and spleen when compared with  those  born  to



pigs  fed  30.6 mg CN~/kg  diet.  Sows treated at  all levels had  hyperplasla



of  the  glomerull  (Tewe and  Maner, 1981b).   Teratogenlc  affects per  se  were



not reported 1n either  of these studies.



3.3.2.   Inhalation.    Pertinent   data   regarding   the   teratogenlcHy   of



Inhaled cyanide could not be located  1n  the available literature.



3.4.   TOXICANT INTERACTIONS



    Since cyanide 1s a known Inhibitor  of  cytochrome  oxldase, compounds  such



as  sulflde  or azlde,  which  also Inhibit  cytochrome  oxldase,  may  synerglze



with  cyanide  (Nlcholls,  1975;  Smith   et  al.,  1977).   VHamln  C  may  also



enhance the  toxldty of cyanide.  Basu  (1983) treated a  group of guinea  pigs



first  with  vitamin  C, then  with potassium  cyanide,  and another group  only



with  potassium cyanide.   VHamln C-treated animals  had  a 100%  Incidence  of



severe  tremors, ataxla,  muscle twitches, paralysis and  convulsion.   Animals



exposed only to potassium cyanide had a 38%  Incidence of these  symptoms.   It
                                     -13-

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was hypothesized  that  vitamin C may  tie  up cystelne, a sulfur  donor  poten-
tially Involved 1n  the  conversion  of cyanide to thlocyanate,  Its  less  harm-
ful metabolite.
    Compounds  that  generate  methemoglobln  (sodium  nitrate,  amyl  nitrate,
hydroxylamlne  or  methylene  blue)   antagonize  the  toxic  effects  caused  by
cyanide,   since  methemoglobln competes  with cytochrome  oxldase  for  cyanide
(Smith  and  Olson,   1973;   Way,   1981).    Cobalt-containing   compounds   also
antagonize the toxldty of cyanide, since cobalt has  an  affinity for  cyanide
(Mushett  et a!.,  1952;  FMedberg  and Schwarzkopf,  1969;  Davlson,  1969).
                                    -14-

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                             4.  CARCINOGENICITY
4.1.   HUMAN DATA
4.1.1.   Oral.    Pertinent  data  regarding  the  cardnogenldty   of   orally
Ingested  cyanide (hydrogen  cyanide,  potassium  cyanide  or  sodium cyanide)
could not be located 1n the available  literature.
4.1.2.   Inhalation.   Pertinent  data   regarding  the  cardnogenldty   of
Inhaled cyanide could not be located 1n  the available  literature.
4.2.   BIOASSAYS
4.2.1.   Oral.    Pertinent  data  regarding  the  cardnogenldty   of   orally
administered cyanide could not  be located 1n the available literature.
4.2.2.   Inhalation.   Pertinent  data   regarding  the  cardnogenldty   of
Inhaled cyanide could not be located 1n  the available  literature.
4.3.   OTHER RELEVANT DATA
    Of  the  three mutagenldty  studies  located  1n the  available  literature,
two were negative and  one was marginally  positive.  De  Flora  (1981) reported
that  potassium  cyanide  was not mutagenlc  to  five  strains  of   Salmonella
typhlmuMum, regardless of the  presence or  absence of  S-9  (mammalian  activa-
tion  system).   Karube et al.  (1981)  also  reported  negative  results   from  a
rec-assay In Bacillus  subtlHs.   Kushl  et al. (1983) reported  that hydrogen
cyanide gas  was  marginally  mutagenlc  to Salmonella typhlmurlum strain  TA100
1n  the  absence of  S-9, but not  mutagenlc  to  strain  TA98 1n the  presence  or
absence of S-9.
    Tewe  and  Maner  (1981a)   reported   that   no  teratogenlc   effects were
observed when  Wlstar rats were exposed to 500  ppm of  cyanide 1n the diet
throughout pregnancy;  however,  Tewe and Maner (1981b)  reported that  fetuses
of  pigs  fed  276.6  or  520.7 mg  CN  (as KCN)/kg diet throughout  pregnancy had
reduced ratios  of  organ  weight to  body weight.   At  these levels, sows had
kidney hyperplasla  and morphological changes 1n  thyroid  cells.

                                     -15-

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4.4.   WEIGHT OF EVIDENCE
    IARC has not evaluated  the  risk  to humans associated with oral or  Inha-
lation exposure  to  cyanide.   Since data are  lacking regarding the cardno-
genlcHy of cyanides to animals or humans, applying  the  criteria  proposed by
the Carcinogen Assessment Group of the U.S. EPA  (Federal  Register,  1984} for
evaluating  the  overall  weight  of  evidence  of  cardnogenlclty  to  humans,
cyanide Is most  appropriately designated  a  Group  D-Not  Classified  chemical.
                                    -16-

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                     5.   REGULATORY  STANDARDS AND  CRITERIA
            *

    FAO and  WHO  have established an  Interim ADI  for cyanide In  food  of  3.5
mg/man/day,  assuming  a  70  kg  man  (U.S.  EPA,  1980a).   In  the  June 9,  1981
Errata for  Ambient  Water  Quality Criteria (U.S.  EPA,  1980a), an  Interim ADI
of  7.56  mg CN~/day water  was  established,  based on  a NOAEL of  10.8  mg/kg/
day derived  from  the  chronic  study of Howard  and Hanzal  (1955)  (see Section
3.2.1.}.   In the calculation of  this  value, an uncertainty  factor of 100 was
used.   In  addition,  an  average  body  weight of 70 kg  and consumption  of  2 i
water/day and 6.5 g fish/day were assumed.
    The  U.S.  Public  Health  Service  (1962)  has  recommended  that  levels  of
cyanide 1n water not exceed 0.2 mg/a.
    ACGIH  (1983)  has recommended  a  TWA-TLV  of  5  mg/m3 for cyanides,  with
the Indication  that  dermal absorption may  also be  Involved.  This  value 1s
based  on  Irritation  to  the respiratory  system  and  1s Intended  to  protect
from the  effects  of  chronic exposure to  hydrogen cyanide  (derived primarily
from the  report  by El Ghawabl  et  al.,  1975).   NIOSH  (1976) and  OSHA  (1981)
have also adopted this value as a recommended  standard
    Tolerances have been set for  residues of hydrogen cyanide when used as a
post-harvest Insecticide  fumlgant.   Those tolerances  have  been  presented 1n
Table 5-1 (Code of Federal Regulations,  1982).
                                     -17-

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                                   TABLE  5-1

                 Tolerances  for  Hydrogen  Cyanide  1n  Foodstuffs
                     When  Used as  a Post-Harvest  Fumigant*
                        Foodstuff                    Tolerance
                                                       (ppm)
               Cereal flours                            125

               Cereals cooked before eaten               90

               Uncooked ham, bacon, sausage              50

               Cocoa                                    200

               Several spices                           250

               Several grains                            75

               Dried beans,  peas,  nuts                   25
*Source:  Code of Federal  Regulations,  1982
                                     -18-

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                              6.   RISK  ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1.   Oral.  Data  from  animal studies  are  Insufficient for  the calcula-
tion  of  an  AIS for subchronlc  oral  exposure to cyanide.  In  the  studies  by
Palmer  and   Olson   (1979),  Tewe  and  Maner  (1980,  1982) and Tewe  (1982),
animals  were exposed  to only  one  level  of  treatment  1n  addition  to  the
control  level of exposure (0  mg  KCN/kg diet).   Furthermore,  Palmer and Olson
(1979)  reported  an Increase  In  liver  weight  1n  animals exposed  to  4 mg/kg
bw/day  1n the diet, but no  effect  on animals  exposed  to the  same dose  via
drinking  water.    While Hayes   (1967)  exposed  rats  to  a  range  of  doses
(0-250),  he  reported  only  mortality.    Effect  levels  cannot  be  established
from these studies.
6.1.2.   Inhalation.   Only   one   subchronlc  animal  study    pertaining   to
cyanide  exposure (Hugod, 1981)  was  located  1n  the  available  literature.   In
this  study,  rabbits were exposed to  a single  level of  hydrogen  cyanide  gas
for only  28 "days.   Furthermore,  the human occupational  exposure  studies  are
lacking  1n quantitative  detail.   Therefore,  these studies cannot  be  used  In
quantitative risk assessment.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1.   Oral.  The U.S.  EPA (1985) has  recently reevaluated  the  data  from
the Howard and  Hanzal  (1955) 2-year  experiment 1n  rats  and used  these  data
to  calculate an  ADI  for  CN~.   The  Drinking  Water  Criteria Document  for
Cyanide  (U.S. EPA,  1985) contains an  1n-depth  discussion  of  the  assumptions
and calculations used  1n derivation  of the ADI.  This  discussion  1s present-
ed here 1n abbreviated form.
                                     -19-

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    The  U.S.  EPA  (1985)  chose  to derive  an ADI  for  CN~  rather  than  HCN
because  CN~  1s presumed  to  be  the  toxic  moiety  1n  cyanide compounds.   In
determining the doses  of  CN~  to  which  the rats  1n  this  study were  exposed
on an mg/kg bw/day  basis,  the average body weights were estimated  using  the
mean body weights at  the  beginning and end of the experiment and the  growth
charts provided by  the Investigators.   Average  body weights  arrived at  by
the  U.S.  EPA   (1985)  were  390 g  and  394 g in low- and  high-dose males  and
232 g and  255  g  1n  low- and  high-dose females, respectively.  Food  consump-
tion was measured by the investigators and  averaged 19.46 g  and  18.50  g/rat/
day  in  the  low- and high-dose males  and  14.69 g  and  17.24 g/rat/day  in  the
low- and high-dose  females,  respectively.   The diets  were prepared by  fumi-
gation and  HCN was measured  1n  the  food  offered to  the  rats.   From  these
data, averaged over the entire treatment period,  the U.S. EPA (1985)  calcu-
lated that  the low-dose diet  contained  73 ppm CN~  and  the high-dose  diet,
160 ppm CN~.
    From the above  data,  the U.S. EPA (1985)  calculated the animal doses  of
CN , expressed as  mg/kg/day,  for  the male and female  rats  In the  low-  and
high-dose groups  as  follows:

    low-dose male:
    73 mg CN'/kg  diet  x 0.01946 kg diet/0.39 kg bw=3.6 mg  CN'/kg  bw/day

    high-dose  male:
    160 mg CNVkg  diet x 0.01850 kg diet/0.394 kg  bw=7.5 mg CNVkg bw/day

    low-dose female:
    73 mg CNVkg  diet  x 0.01469 kg diet/0.232 kg bw=4.6 mg CNVkg  bw/day

    high-dose  female:
    160 mg CN'/kg  diet x 0.01724 kg diet/0.255 kg  bw=10.8 mg  CNVkg  bw/day

                                     -20-

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 Since  effects  were not observed  1n  treated  rats,  the animal dose of 10.8 mg
 CN~/kg  bw/day  calculated  for   high-dose   females   represents  the  highest
 NOEL.   The U.S. EPA  caluclated  an ADI of  1.5  mg CN"/day  for  a  70 kg human
 by  multiplying the  animal  dose,  10.8  CN~/kg bw/day  by 70  kg  and dividing
 by  a UF  of 500.  A  UF of  500  was  chosen  as  follows:   a factor of  10 to
 account for  animal to human extrapolation,  a factor  of 10 to afford greater
 protection  for  unusually  sensitive  Individuals  and  a  final  factor  of  5
 because a criterion  for  drinking  water  was derived from  a  dietary  study.
 Measurements by  the  Investigators demonstrated  that  HCN volatilized from the
 diet  prepared  by  fumigation.   It was  believed  that  the  final  UF of  5  may
 adjust  for the uncertainty  associated  with  volatilization of HCN  from  the
 diet.   The  U.S.   EPA  (1985)  also  suggested  that  absorption  of CN~  from
 drinking water might  be facilitated  but that absorption from the diet may be
 retarded  by  adsorption to food  particles.   The additional  UF of  5  was  also
 Intended  to account for some  of  the uncertainty  associated with this phenom-
 enon.   Since  this ADI (1.5 mg  CN~/day for  a  70 kg human) was  derived  by
 the U.S.  EPA (1985) based  on  the most complete  chronic data available and by
 a rationale that logically addressed  the  Issues  Involved 1n risk assessment,
 this ADI 1s adopted as the AIC for CN~  1n this document.
    A CS  was  calculated for  the effects  observed (degeneration  of  ganglion
 cells 1n  the CNS)   by Herttlng  et al.  (1960) 1n dogs treated by  capsule  for
 15 months  with  NaCN   at 3  mg CN~/kg  bw/day.  A  human MED  was  calculated  by
multiplying the animal dose by the  cube root of  the  ratio of the body  weight
 of dogs (assumed:  14 kg)  to that of humans  (assumed:   70  kg)  and multiply-
 ing the result  by 70  kg  to  express  the MED 1n  mg/day  for a 70  kg man.   A
human MED  of  122.8 mg/day, corresponding  to an  RV   of  2.4,  was  calculated.
                                     -21-

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The  effects  observed  were  assigned  an  RV   of  6,  because  lesions  were
observed  that  were not reported  to  cause a decrement 1n  organ  function.   A
CS of 14.4 was calculated as the product of RVJ and RV .
                                              d       e
6.2.2.   Inhalation.   Only  one  subchronlc  study  pertaining  to exposure  to
cyanide  via  Inhalation (Hugod,  1981)  was  located  1n the  available  litera-
ture.  Since this  study Involved  exposure  of  rabbits  for  only 28 days, deri-
vation of  an AIC  for  chronic exposure  from  these data would  be  Imprudent.
The  TLV  of  5  mg/m3  established  by ACGIH  (1983), however,  can  be  used  to
derive an  Interim ADI  In  the following manner.   Assuming  that  a 70  kg  man
breathes  a  volume  of  10  m3  a1r/8-hour  workday  and  works  5 days/week,  the
TLV  of  5 mg/m3  Is multiplied  by the  product  of  10 mVday  and  5/7  days/
week  to  arrive at  an Inhaled  dose  of  35.7  mg CN~/man/day.  Dividing  this
value by  an  uncertainty  factor  of 10 to account  for  the  range  of  sensitivi-
ties  In  the  human population results  1n an Interim ADI of  3.57 mg  CN"/man/
day.
    This ADI  (3.57  mg 'ClT/man/day)  1s  larger  than the ADI  derived  for  oral
exposure  to  CN~  by the  U.S EPA  (1985).   Since cyanide 1s  readily  absorbed
by  the  pulmonary  system and  since the  first  pass effect of  the liver  (very
Important 1n CN~  detoxification)  1s bypassed  by this route, 1t Is  strongly
recommended that  the  ADI  derived from  the  TLV not be adopted as an  Inhala-
tion ADI for CN~.
6.3.   CARCINOGENIC POTENCY (q.,*)
6.3.1.   Oral.   The lack  of data regarding  the cardnogenldty of  Ingested
cyanide precludes  assessment of  carcinogenic risk.
6.3.2.   Inhalation.   The   lack  of  data regarding  the  cardnogenldty   of
Inhaled cyanide precludes  assessment  of  carcinogenic risk.
                                     -22-

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                                7.  REFERENCES

AC6IH  (American Conference  of Governmental  Industrial  Hyglenlsts). '  1983.
Threshold  Limit Values for  Chemical  Substances and  Physical  Agents In  the
the  Workroom Environment  with Intended  Changes  for  1983-84.  ACGIH,  Cin-
cinnati, OH.  p. 16.

American  Cyanamld   Co.   1959.   Report on  sodium  cyanide:  30-Day  repeated
feeding  to  dogs.   Central  Med. Dept.   Report Number 59-14.   (Cited  in  U.S.
EPA, 1985)

Basu, T.K.   1983.   High-dose  ascorbic  add  decreases  detoxification  of  cyan-
ide  derived from  amygdalin   (laetrile):  Studies  1n  guinea pigs.   Can.  J.
Physlol. Pharmacol.  61(11):  1426-1430.  (Cited 1n  U.S.  EPA,  1985)

Callahan,  M.A., M.W.   Slimak,  N.W.   Gabel,  et  al.   1979.   Water-Related
Environmental Fate  of  129  Priority Pollutants, Vol. 1.   U.S.  EPA, Office  of
Water Planning  and  Standards, Office of Water  and  Waste Management,  Washing-
ton, DC.  EPA 440/4-79-0292a.

Carmelo,  S.  1955.    New  contributions  to  the  study  of  subacute-chronlc
hydrocyanic add intoxication  in  man.   Rass Med. Ind.  24:  254-271.  (Cited
1n U.S.  EPA, 1985)

Code of  Federal  Regulations.   1982.  Hydrogen  cyanide.   21  CRT  93.236.

Davison, V.  1969.   Cyanide poisoning.  Occup.  Health.  21:  306-308.  (Cited
1n U.S.  EPA, 1985)

                                     -23-

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De  Flora,  S.  1981.   Study of  106  organic and  Inorganic  compounds 1n  the



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                                     -24-

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FMedberg,  K.D.  and  H.A.  Schwarzkopf.   1969.   Blausaureexhalatlon  be1  der
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                                     -25-

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Howard,  J.W.  and  R.F.  Hanzal.   1955.  Chronic  toxldty for  rats  of  food
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                                     -26-

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                                     -27-

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                                     -28-

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                                     -29-

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                                     -30-

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                                     -31-

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Wokes, F.   1958.   Tobacco amblyopla.   Lancet.  2:  526-527.   (Cited 1n U.S.
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                                     -32-

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                                                      APPENDIX

                                              Summary Table for Cyanide
                    Species
                             Experimental
                            Dose/Exposure
Effect
Acceptable Intake
  (AIS or AIC)
Reference
     Inhalation

       AIS

       AIC
                                                                   NO

                                                                   ND
i
CO
CO
Oral

  AIS

  AIC
                     rats       160 mg  CNVkg
                                diet, 10.8  mg
                                CNVkg  bw/day
                                In females;  data
                                of Investigators
                                                none
                ND

                1.5 mg/day
                         Howard and
                         Hanzal, 1955;
                         U.S. EPA,  1985
Maximum dogs 3 mg CN~/kg
composite
score
bw/day for 15
months (RVd=2.4)
degeneration of 14.4
ganglion cells
In CNS (RVe=6)
Meriting
et al.,1960

     ND = Not derived

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