Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 2 (2002) / Chapter Skim
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Appendix 5: Hydrogen Cyanide
Appendix 5: Hydrogen Cyanide
Pages 211-276
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From page 211... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels.
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Inhalation studies resulting in sublethal effects, such as incapacitation, and changes in respiratory and cardiac parameters were described for the monkey, dog, rat, and mouse; lethality studies were available for the rat, mouse, and rabbit. Exposure durations ranged from a few seconds to 24 hours (h)
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Because no specific susceptible populations were described following chronic exposures or during use of nitroprusside solutions to treat chronic hypertension, the potential differences in susceptibility among humans are not expected to exceed 3-fold. The 8-h AEGL-1 value was derived from a consideration of the doseresponse data obtained from all of the monitoring studies cited and subsequently time-scared to the shorter AEGL exposure durations.
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ppm, respectively, is supported by monitoring studies in which chronic exposures to average concentrations of ~ to 10 ppm may have produced primarily reversible central nervous system effects such as headaches in some workers (El Ghawabi et al.
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. The safety of the 4- and 8-h AEGL-3 values of 8.6 and 6.6 ppm is supported by the lack of severe adverse effects in healthy workers chronically exposed to similar values during monitoring studies (Grabois 1954; El Ghawabi et al.
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1975) AEGL-2 17 10 7.1 3.5 2.5 Slight central nervous (Disabling)
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Information on human exposures was limited to exposures to high concentrations for short time intervals, poorly documented accidental exposures, and chronic occupational exposures. TABLE 5-2 Chemical and Physical Data Parameter Value Reference ACGIH 1996 Synonyms Molecular formula Structure Molecular weight CAS registry number Physical state Color Solubility in water Vapor pressure Vapor density (air = 1)
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2.~. Acute Lethality Although a great many deaths have occurred from accidental, intentional, or occupational exposures to HCN, in only a few cases are specific exposure concentrations known.
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Adverse health consequences on systems other than the central nervous and respiratory systems have been documented during occupational and/or accidental exposures. Generally, these effects occurred following chronic exposures, but the cardiovascular and dermal effects could occur following acute exposures.
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1980 Work area: 0.2 soning Geometric mean No clear exposure related symp- Leeser et al. 1990 values of personal tome or adverse health effects; samples: 0.03-0.96 employment for 1-40 y (range: 0.01-3.3)
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. The N~C Subcommittee on Spacecraft Maximum Allowable Concentrations, in evaluating the El Ghawabi et al.
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In both facilities, urinary thiocyanate levels of workers were higher after work than prior to work, were higher in smokers than in nonsmokers, and increased with the number of years of work. Urinary
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. Blood and urinary cyanide and thiocyanate levels varied widely among the groups, and there was no clear relationship to occupational exposure at these concentrations; blood cyanide levels did not bear a relationship to exposure via smoking, but free thiocyanate levels in the urine tended to be higher in smokers than in nonsmokers.
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, and for current smokers, the blood cyanide level was actually higher in the control group (2.94 ,umol for cyanide workers who smoked; 3.14 ,umol for controls who smoked)
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Acute exposures that failed to result in mortality were either to high concentrations for very short exposure durations (approximately 500 or 450 ppm for approximately 1.5 min or 6 min. respectively [Barcroft 1931; Bonsall 19844)
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~ 950) , and some symptoms associated with chronic exposures may be attributed to thyroid effects.
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For all exposure durations, deaths occurred during exposures or within ~ ~ postexposure. The LCso values for the 5-, 15-, 30-, and 60-min exposure periods for the unrestrained rats were 369 ppm (95% CL, 350-395 ppm)
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228 ACUTE EXPOSURE GUIDEL/NE LEVELS FOR SELECTED A/RBORNE CHEM/CALS TABLE 5-4 Summary of Acute Lethal Inhalation Data in Laboratory Animals Concentration Exposure Species (ppm) Time Eftecta Reference _ Dog 115 Not given Fatal Dudley et al.
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(higher toxicity) for restrained rats: 39S, 163, 85, and 63 ppm for the respective exposure durations.
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At exposure concentrations of 500 and 750 ppm, the mean times to death were 12 min and 2 min. respectively.
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Acute exposure data were available for the monkey, rat, and mouse with exposure durations ranging from 5 min to 24 h. Limited data were available for the dog.
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Several heart, blood, muscular, and central nervous system parameters were measured before, during, and after the exposures. At 60 ppm, there was a slight depressive effect on the central nervous system, as evidenced by changes in brain wave activity at the end ofthe exposure periods (indicated in electroencephalograms tEEGs]
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233 Cal Cal U
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Respiratory rates were measured in restrained rats during all exposure durations (5-60 min)
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measured incapacitation times for groups of eight female ~c! ICR mice inhaling various HCN concentrations.
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In addition to sodium cyanide, aliphatic nitrites and cyanogenic glycosides have been demonstrated to be teratogenic to golden hamsters by the oral and inhalation routes (WilIhite 1981, 1982; WilThite and Smith 1981; WilThite et al. 1981; Frakes et al.
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The average ~ -h LC50 value for the rat was ~ 34 ppm. The LCso values tend to be similar for the mouse and rat, and the mouse was slightly more sensitive in accordance with its slightly smaller body size and higher relative respiratory rate.
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HCN in the blood is almost completely contained in the red blood cells where it is bound to methemogiobin. Immediately after infusion of sodium nitroprusside into patients, 98.4% of the blood cyanide was found in the red blood cells (Vesey et al.
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The mean concentration of whole blood cyanide in rabbits that died following inhalation exposure was 170 ,ug/lOO mL; the mean plasma concentration was 48 ,ug/IOO rnE (BalIantyne 1983~. Plasma levels of cyanide in unexposed, healthy adults average O to 10.7 ,ug/IOO ml (mean, 4.8 ,ug/IOO mL)
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(1947) studied the effect of intravenously administered sodium cyanide on the electrocardiogram of ~ 6 soldiers.
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Found no relationship between exposure and blood cyanide levels Blood CN- of control nonsmokers ranged from 3.5-10.1 ~g/100mL Blood CN- of control smokers ranged from 2.0-13.0 ,ug/100mL Blood CN- of control and cyanide-exposed workers combined ranged from 2.0-15 ,ug/100mL (Separate data were not provided for cyanide workers)
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l because time to death is not useful in determining exposure concentration-duration relationships but is useful for determining relative species sensitivity. Relative to body weight, humans have a much lower respiratory rate and cardiac output than rodents.
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As noted in Section 4.4.1, the enzyme rhodanese is present to a large excess in the human body relative to its substrates, thus demonstrating zero
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states that at 150 to 250 ,umol/L of"erythrocyte concentrate" headaches, palpitations, and hyperventilation occur. Unfortunately, blood cyanide levels were ex
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Several lethality studies conducted over various exposure durations were available for calculation of concentration-exposure duration relationships. Using the animal lethality data of Barcroft (193 I)
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Three monitoring studies, involving no symptoms to mild symptoms during chronic occupational exposures of adult mates, are relevant to development of AEGL-1 values. The symptoms and blood concentrations of cyanide in the monitoring study of Chandra et al.
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Higher blood cyanide levels were correlated with the higher exposure levels in the fall of the year. The results of clinical histories and medical examinations showed no differences to only minor differences for a variety of parameters between the HCN workers and a matched control group.
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The AEGL-! was derived from a consideration ofthe dose-response data, which were obtained from all ofthe monitoring studies and subsequently time scaled to the shorter exposure durations.
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DATA ANALYSIS FOR AEGL-2 6.~. Human Data Relevant to AEGL-2 As noted above for the AEGL-l, chronic occupational exposure of adult males to >10 ppm produced symptoms of headache, weakness, changes in taste and smell, irritation of the throat, vomiting, and effort dyspnea (El Ghawabi et al.
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Although this end point (a slight depressive effect on the central nervous system as evidenced by a change in brain-wave activity near the end of the exposure) was a NOAEL for the definition of an AEGL-2, it was chosen because the next higher experimental concentration resulted in severe adverse effects of incapacitation, unconsciousness, and possibly death.
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DATA ANALYSIS FOR AEGL-3 7.~. B:uman Data Relevant to AEGL-3 No human studies of sufficient exposure duration with measured concentrations producing irreversible or life-threatening effects were located in the available literature.
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Human accidental and occupational exposures indicate that there are individual differences in sensitivity to HCN, but the magnitude of these differences does not appear to be great. No specific data on susceptible populations were located in numerous published monitoring studies or during the clinical use of nitroprusside solutions to control hypertension.
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From page 254... ...
The 30 ppm concentration divided by a total UP of 6 and scaled across time from 24 h to 30 min using C26 x t = k results in a 30-min AEGL-2 of 22 ppm. The AEGL values are also supported by the study of Parmenter (1926)
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The subcommittee suggested that the average concentration of "~.0 ppm in the three plants would likely produce no more than mild CNS effects (e.g., mild headache) , which would be acceptable for 1-hour exposures in a spacecraft." The subcommittee concluded that it was "likely that the more serious symptoms, such as vomiting, were the result of brief exposures to high HCN concentrations." Therefore, ~ ppm was identified as the 1-h allowable concentration of HCN.
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The ERPG-3 for HCN is based on several animal studies, including Purser (1984) , in which exposures up to 60 ppm caused only reversible effects.
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Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AIHA, American Industrial Hygiene Association; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Health and Safety Administration.
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8.3. Data Adequacy and Research Needs The data base from animal studies is robust, but there are little definitive data on human exposure concentrations for short exposure durations and no definitive data on differences in susceptibilities among adults or between adults, infants, and children, other than well-understood ventilatory differences in the latter case.
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Taken together, the data indicate that the HCN AEGL values may be conservative. However, data on infants, chicken, and the elderly, populations that may be more susceptible to HCN toxicity than healthy adults based on higher respiration rates and slower metabolism, among other factors, are lacking.
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1980. Chronic cyanide exposure - A biochemical and industrial hygiene study.
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1954. Effect of injected sodium cyanide on newborn and adult mice.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1982. Cyanide toxicity of sodium nitroprusside in therapeutic use with and without sodium thiosulphate.
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1991. Validity of salivary thiocyanate as an indicator of cyanide exposure from smoking.
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Appendixes
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266 ACUTE EXPOSURE GUIDELINE LEVELS FOR SELECTED AIRBORNE CHEMICALS APPENDIX A TIME-SCALING CALCULATIONS FOR HYDROGEN CYANIDE Best Fit Concentration x Time Curve 2.1 2.05 0.9 1 1.1 Log Time (minutes) FIGURE A-1 Regression line for incapacitation in monkeys (data of Purser et al.
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HYDROGEN CYANIDE 267 Best Fit Concentration x Time Curse c cat c 2.4 o To 2.3 A) J 0.6 0.8 1 1.2 Log Time (minutes)
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1975; Hardy et al. 1950; Grabois 1954; Maehlyand Swensson 1970; Toxicity end point: No adverse effect in healthy adult humans occupationally exposed at geometric mean concentration of < ~ (range 0.01-3.3 ppm, personal samplers tup to 6 ppm, area sam ples]
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. OXlClty end point: Slight central nervous system depression in monkeys inhaling 60 ppm for 30 min.
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'2= 2.5 ppm Derivation of AEGL-3 Key study: E.~. du Pont de Nemours 1981 Toxicity end point: 15-min LCOl of 138 ppm in the rat 30-min LCOl of 127 ppm in the rat 1-h LCO!
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Med.242:968-972. Test Species/Strain/Number: Occupational exposures/63 employees, mean age 44.7 (Leeser et al.
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A factor of 3 was applied to the supporting studies as no specific susceptible populations were identified in monitoring studies or during the clinical use of nitroprusside solutions to control hypertension. The detoxifying enzyme rhodanese is present in all individuals including newborns.
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Intraspecies: 3 - No specific susceptible populations were identified during monitoring studies or during the clinical use of nitroprusside solutions to control hypertension. The detoxifying enzyme rhodanese is present in all individuals, including newboms.
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2. Humans inhaling mean concentrations at 10 or 15 ppm in electroplating or silver-reclaiming factories for up to 15 y reported symptoms including headache, fatigue, effort dyspnea, and syncopes.
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Intraspecies: 3 - No specific susceptible populations were identified during monitoring studies or during the clinical use of nitroprusside solutions to control hypertension. The detoxifying enzyme rhodanese is present in all individuals, including newborns.
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From page 276... ...
Data adequacy: The study was well conducted. The HCN concentrations were continuously monitored using infrared spectrophotometry and validated by gas chromatography.
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