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Cyanide, free
CASRN 57-12-5
Contents
0031
Cyanide, free; CASRN 57-12-5
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Cyanide, free
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 02/01/1993
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 03/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Cyanide, free
CASRN -- 57-12-5
Last Revised -- 02/01/1993
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
Rat Chronic Oral NOAEL: 10.8 mg/kg/day 100 5 2E-2
Study cyanide mg/kg/day
Howard and Hanzal,
1955
Weight loss, thyroid LOAEL: 30 mg/kg/day
effects and myelin cyanide
degeneration
Rat Subchronic to
Chronic Oral Bioassay
Philbrick et al., 1979
*Conversion Factors: none
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Howard, J.W. and R.F. Hanzal. 1955. Chronic toxicity to rats of food treated
with hydrogen cyanide. J. Agric. Food Chem. 3: 325-329.
Philbrick, D.J., J.B. Hopkins, D.C. Hill, J.C. Alexander and R.G. Thomson.
1979. Effects of prolonged cyanide and thiocyanate feeding in rats. J.
Toxicol. Environ. Health. 5: 579-592.
Hydrogen cyanide (HCN) is soluble in water and dilute acid (which includes the
gastric environment) and is readily hydrolyzed to 1 molar equivalent of
cyanide (CN) and 1 molar equivalent of hydrogen (Hartung, 1982).
In this 2-year dietary study, rats (10/sex/group) were administered food
fumigated with HCN. The average daily concentrations were 73 and 183 mg CN/kg
diet. From the data reported on food consumption and body weight, daily
estimated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN
concentrations were estimated based on the authors' data for concentration at
the beginning and end of each food preparation period and by assuming a first-
order rate of loss for the intervening period. There were no treatment
related effects on growth rate, no gross signs of toxicity, and no
histopathologic lesions.
Studies by Philbrick et al. (1979) showed decreased weight gain and thyroxin
levels and myelin degeneration in rats at 30 mg/kg/day CN. Other chronic
studies either gave higher effect levels or used the subcutaneous route
(Crampton et al., 1979; Lessell, 1971; Hertting et al., 1960). Human data do
not provide adequate information from which to derive an RfD because effective
dose levels of chronically ingested CN are not documented. Therefore, the
study of Howard and Hanzel (1955) provides the highest NOAEL, 10.8 mg/kg/day
for CN, and is chosen for the derivation of an RfD for CN of 1.5 mg/day or
0.02 mg/kg/day.
Cyanide is metabolized extensively in the liver, indicating that the only
relevant route of administration for quantitative risk assessment in the
derivation of an oral RfD is the oral route of administration.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- According to the U.S. EPA (1985), an uncertainty factor of 100 is used
to derive the RfD (10 for species extrapolation, 10 for sensitive population).
MF -- A modifying factor of 5 is used to account for the apparent tolerance to
cyanide when it is ingested with food rather than when it is administered by
gavage or by drinking water.
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Decreased protein efficiency ratio was produced by dietary cyanide treatment
of rats during gestation, lactation and postweaning growth phase in the Tewe
and Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/ day)
producing that effect is slightly lower than the currently accepted NOAEL of
10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested
sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of
glomerular cells of the kidneys and reduced activity of the thyroid glands in
the gilts. However, the number of animals in this experiment was very small.
A Japanese study (Amo, 1973) indicated that 0.05 mg/ kg/day of cyanide
obtained from drinking water decreased the fertility rate and survival rate in
the F1 generation and produced 100% mortality in the F2 generation in mice.
However, these data are not consistent with the body of available literature.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
The confidence in the study is medium because adequate records of food
consumption and body weight were maintained and animals of both sexes were
tested at two doses for 2 years. The data base is rated medium because a
small but sufficient number of studies support the chosen study. Medium
confidence in the RfD follows. Additional chronic/reproductive studies are
needed to support a higher level of confidence in the RfD.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
U.S. EPA. 1984. Health Effects Assessment for Cyanides. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial
Response, Washington, DC.
U.S. EPA. 1985. Drinking Water Criteria Document for Cyanides. Office of
Drinking Water, Washington, DC.
The ODW criteria document and OERR health effects assessment have both had
extensive Agency-wide and limited external review.
Agency Work Group Review -- 08/05/1985
Verification Date -- 08/05/1985
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Cyanide, free
CASRN -- 57-12-5
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Cyanide, free
CASRN -- 57-12-5
Last Revised -- 03/01/1991
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as a human carcinogen.
Basis -- Pertinent data regarding carcinogenicity have not been located in
the available literature.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
None.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
In vitro studies of genotoxicity have been negative except for a
marginally mutagenic response for HCN in Salmonella typhimurium strain TA100
(Kushi et al., 1983). This response was decreased in the presence of rat
hepatic homogenates.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1987
The 1987 Drinking Water Criteria Document on Cyanide has received OHEA review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 03/23/1988
Verification Date -- 03/23/1988
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Cyanide, free
CASRN -- 57-12-5
Last Revised -- 01/01/1990
__VI.A. ORAL RfD REFERENCES
Amo, H. 1973. Effects of oral administration of cyanide and heavy metals in
long term on breeding and chromosomes analyses of mice. Nagoya shiritsu
Diagaku Igakkai Zasshi. 24(1): 48-66.
Crampton, R.F., I.F. Gaunt, R. Harris et al. 1979. Effects of low cobalamin
diet and chronic cyanide toxicity. Toxicology. 12: 221-234.
Hartung, R. 1982. Cyanides and nitriles. In: Patty's Industrial Hygiene and
Toxicology, 3rd revised ed., Vol. 2c, G.D. Clayton and F.E. Clayton, Ed. John
Wiley and Sons, Inc., NY. p. 4845-4900.
Hertting, G., O. Kraupp, E. Schnetz and S. Weeketich. 1960. Untersuchungen
uber die Folgen einer chronischen Verabreichung akut toxischer Dosen von
Natrimcyanid an Hunden. Acta Pharmacol. Toxicol. 17: 27-43.
Howard, J.W. and R.F. Hanzal. 1955. Chronic toxicity for rats of food
treated with hydrogen cyanide. Agric. Food Chem. 3: 325-329.
Lessell, S. 1971. Experimental cyanide optic neuropathy. Arch. Opthalmol.
86(2): 194-204.
Philbrick, D.J., J.B. Hopkins, D.C. Hill, J.C. Alexander and R.G. Thomson.
1979. Effects of prolonged cyanide and thiocyanate feeding in rats. J.
Toxicol. Environ. Health. 5: 579-592.
Tewe, O.O. and J.H. Maner. 1981a. Long-term and carry-over effect of dietary
inorganic cyanide (KNC) in the life cycle performance and metabolism of rats.
Toxicol. Appl. Pharmacol. 58: 1-7.
Tewe, O.O. and J.H. Maner. 1981b. Performance and pathophysiological changes
in pregnant pigs fed cassava diets containing different levels of cyanide.
Res. Veter. Sci. 30: 147-151.
U.S. EPA. 1984. Health Effects Assessment for Cyanides. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial
Response, Washington, DC.
U.S. EPA. 1985. Drinking Water Criteria Document for Cyanides. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment, Cincinnati, OH for the Office of Drinking Water, Washington, DC.
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Kushi, A., T. Matsumoto and D. Yoshida. 1983. Mutagen from the gaseous
phase of protein pyrolyzate. Agric. Biol. Chem. 47(9): 1979-1982.
U.S. EPA. 1987. Drinking Water Criteria Document for Cyanide. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. External Review Draft.
_VII. REVISION HISTORY
Substance Name -- Cyanide, free
CASRN -- 57-12-5
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Date Section Description
-------- -------- --------------------------------------------------------
03/31/1987 IV.B. RQ - new rationale text
03/01/1988 I.A.5. Confidence levels revised
03/01/1988 III.A. Health Advisory added
09/07/1988 II. Carcinogen summary on-line
01/01/1990 VI. Bibliography on-line
08/01/1990 III.A.10 Primary contact changed
08/01/1990 IV.F.1. EPA contact changed
03/01/1991 II.D.3. EPA contacts changed
01/01/1992 I.A.7. Primary contact changed
01/01/1992 IV. Regulatory actions updated
02/01/1993 I.A.7. Minor text change
VIII. SYNONYMS
Substance Name -- Cyanide, free
CASRN -- 57-12-5
Last Revised -- 01/31/1987
57-12-5
CARBON NITRIDE ION
CYANIDE
CYANIDE ANION
Cyanide, free
CYANIDE ION
CYANURE
FREE CYANIDE
ISOCYANIDE
RCRA WASTE NUMBER P030
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0031.HTM
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