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
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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.
-------
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
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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).
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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.
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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.
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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).
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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
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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.
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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
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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.
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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.
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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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