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Cyanogen (CASRN 460-19-5)

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Cyanogen; CASRN 460-19-5

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 Cyanogen

File First On-Line 01/31/1987

Category (section)
Status
Last Revised
Oral RfD Assessment (I.A.) on-line 12/01/1989
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) no data

_I.  Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Cyanogen
CASRN — 460-19-5
Last Revised — 12/01/1989

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

No adverse effects

Rat Chronic Oral Study

Howard and Hanzal, 1955

NOAEL: 10.8 mg/kg/day
cyanide converted to
21.6 mg/kg/day of
cyanogen
100
5
4E-2
mg/kg/day

Weight loss, thyroid
effects and myelin
degeneration

Rat Subchronic to
Chronic Oral Bioassay

Philbrick et al., 1979

LOAEL: 30 mg/kg/day
cyanide
(60 mg/kg/day cyanogen)

     

*Conversion Factors -- molecular weight conversion factor = 52/26 [MW C2N2 = 52; MW CN = 26]

__I.A.2. Principal and Supporting Studies (Oral RfD)

Howard, J.W. and R.F. Hanzal. 1955. Chronic toxicity for rats of food treated with hydrogen cyanide. 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.

The toxicity of cyanogen, itself, has not been assessed. This risk assessment is based on the toxicity of the cyanide (CN) ion. Cyanogen does not completely dissociate into free cyanide in water or dilute acetic acid. The RfD for this compound is derived from the RfD of free cyanide on an equimolar basis, assuming that cyanogen releases only one molar equivalent of free cyanide.

In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with hydrogen cyanide. 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 histopathological 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 cyanide are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL, 10.8 mg/kg/day for cyanide, and is chosen for the derivation of an RfD for cyanide 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 Studies/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
Database — 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 database 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

Source Document — U.S. EPA, 1985

Other EPA Documentation — None

Agency Work Group Review — 08/05/1985

Verification Date — 08/05/1985

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Cyanogen conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__I.A.7. EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

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_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — Cyanogen
CASRN — 460-19-5

Not available at this time.

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_II.  Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Cyanogen
CASRN — 460-19-5

This substance/agent has not undergone a complete evaluation and determination under US EPA's IRIS program for evidence of human carcinogenic potential.

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_III.  [reserved]
_IV.  [reserved]
_V.  [reserved]


_VI.  Bibliography

Substance Name — Cyanogen
CASRN — 460-19-5
Last Revised — 12/01/1989

_VI.A. Oral RfD References

Amo, H. 1973. Effects of oral administration of cyanide and heavy metals in long term on breeding and chromosome analyses of mice. Nagoya Shiritsu Diagaku Igakkai Zasshi. 24(1): 48-66.

Crampton, R.E., I.F. Gaunt, R. Harris et al. 1979. Effect of low cobalamin diet and chronic cyanide toxicity in baboons. Toxicology. 12: 221-234.

Hertting, G., O. Kraupp, E. Schnetz and S. Weeketich. 1960. Untersuchungen uber die folgen einer chronischen verabreichung akut toxischer dosen von naturimcyanid. Octa 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 neuropathy. Arch. Opthalmol. 86: 194-204.

Philbrick, D.J., J.B. Hopkins, D.C. Hill, J.C. Alexander and R.G. Thomson. 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 (KCN) 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. Vet. Sci. 30: 147-151.

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

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_VI.B. Inhalation RfC References

None

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_VI.C. Carcinogenicity Assessment References

None

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_VII.  Revision History

Substance Name — Cyanogen
CASRN — 460-19-5

Date
Section
Description
03/31/1987 I.A.6. Documentation corrected
03/01/1988 I.A.5. Confidence levels revised
12/01/1989 I.A.1. Critical effect clarified
12/01/1989 I.A.2. Co-principal study added
12/01/1989 I.A.6. EPA documentation added
12/01/1989 VI. Bibliography on-line
01/01/1992 I.A.7. Primary contact changed
01/01/1992 IV. Regulatory action updated
04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information.
12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added.

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_VIII.  Synonyms

Substance Name — Cyanogen
CASRN — 460-19-5
Last Revised — 01/31/1987

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